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Hep-G2

RRID:CVCL_0027

Organism

Homo sapiens

Comments

Problematic cell line: Misidentified. Originally thought to be a hepatocellular carcinoma cell line but shown to be from an hepatoblastoma (PubMed=19751877). Part of: Cancer Cell Line Encyclopedia (CCLE) project. Part of: ENCODE project common cell types; tier 1. Part of: JFCR45 cancer cell line panel. Part of: MD Anderson Cell Lines Project. Doubling time: ~50-60 hours (DSMZ). HLA typing: A*02:01,24:02; B*35:14,51:01; C*04:01,16:02 (PubMed=25960936). HLA typing: A*02:01,24:02; B*35,51:01; C*04:01,16:02; DQA1*01:02; DQB1*05:02,06:04; DRB1*13:02,16:02 (PubMed=9178645). Sequence variation: NRAS p.Gln61Leu (c.182A>T) (PubMed=8389256; PubMed=12068308). Sequence variation: TERT c.228C>T (-124C>T); in promoter (PubMed=31068700). Omics: Deep antibody staining analysis. Omics: Deep exome analysis. Omics: Deep phosphoproteome analysis. Omics: Deep proteome analysis. Omics: Deep RNAseq analysis. Omics: DNA methylation analysis. Omics: Genome sequenced. Omics: H3K27ac ChIP-seq epigenome analysis. Omics: H3K27me3 ChIP-seq epigenome analysis. Omics: H3K36me3 ChIP-seq epigenome analysis. Omics: H3K4me1 ChIP-seq epigenome analysis. Omics: H3K4me2 ChIP-seq epigenome analysis. Omics: H3K4me3 ChIP-seq epigenome analysis. Omics: H3K79me2 ChIP-seq epigenome analysis. Omics: H3K9ac ChIP-seq epigenome analysis. Omics: H3K9me3 ChIP-seq epigenome analysis. Omics: H4K20me1 ChIP-seq epigenome analysis. Omics: Metabolome analysis. Omics: Protein expression by reverse-phase protein arrays. Omics: Secretome proteome analysis. Omics: SNP array analysis. Omics: Transcriptome analysis. Omics: Virome analysis using proteomics. Genome ancestry: African=71.82%; Native American=0.52%; East Asian, North=3.16%; East Asian, South=0%; South Asian=0%; European, North=8.8%; European, South=15.69% (PubMed=30894373). Discontinued: JCRB; NIHS0326. Discontinued: RCB; RCB0459. DT Created: 04-04-12; Last updated: 05-07-19; Version: 30

Proper Citation

TKG Cat# TKG 0205, RRID:CVCL_0027

Category

Cancer cell line DT Created: 04-04-12; Last updated: 05-07-19; Version: 30

Sex

DT Created: 04-04-12; Last updated: 05-07-19; Version: 30

Synonyms

HEP-G2, Hep G2, HEP G2, HepG2, HEPG2 DT Created: 04-04-12, Last updated: 05-07-19, Version: 30

Vendor

TKG

Cat Num

TKG 0205

Cross References

BTO; BTO:0000599 CLO; CLO_0003704 CLO; CLO_0003713 CLO; CLO_0050856 CLO; CLO_0050858 EFO; EFO_0001187 MCCL; MCC:0000222 CLDB; cl1635 CLDB; cl1636 CLDB; cl1637 CLDB; cl1638 CLDB; cl1639 CLDB; cl1641 CLDB; cl1642 CLDB; cl1643 CLDB; cl1644 CLDB; cl4910 AddexBio; C0015002/46 ArrayExpress; E-MTAB-2706 ArrayExpress; E-MTAB-2770 ATCC; HB-8065 BCRC; 60025 BCRJ; 0103 BioSample; SAMN01821557 BioSample; SAMN01821681 BioSample; SAMN03472183 BioSample; SAMN10988201 CCLE; HEPG2_LIVER CCRID; 3111C0001CCC000035 CCRID; 3131C0001000700072 CCRID; 3142C0001000000024 CCTCC; GDC0024 Cell_Model_Passport; SIDM00904 CGH-DB; 9068-4 ChEMBL-Cells; CHEMBL3307718 ChEMBL-Targets; CHEMBL395 CLS; 300198/p2277_Hep-G2 Cosmic; 690746 Cosmic; 724821 Cosmic; 852774 Cosmic; 869169 Cosmic; 869298 Cosmic; 871510 Cosmic; 873392 Cosmic; 873713 Cosmic; 928138 Cosmic; 932989 Cosmic; 934550 Cosmic; 945158 Cosmic; 948062 Cosmic; 979732 Cosmic; 999850 Cosmic; 1060080 Cosmic; 1187331 Cosmic; 1351511 Cosmic; 1499246 Cosmic; 1518227 Cosmic; 1628386 Cosmic; 2162525 Cosmic; 2301556 Cosmic; 2321029 Cosmic; 2560244 Cosmic; 2668285 Cosmic; 2674233 DepMap; ACH-000739 DSMZ; ACC-180 ECACC; 85011430 ENCODE; ENCBS002KIX ENCODE; ENCBS005NKZ ENCODE; ENCBS006INV ENCODE; ENCBS009AVS ENCODE; ENCBS011NDE ENCODE; ENCBS012DTZ ENCODE; ENCBS013LLU ENCODE; ENCBS015PAC ENCODE; ENCBS016WDR ENCODE; ENCBS017VYZ ENCODE; ENCBS018WXY ENCODE; ENCBS019LAC ENCODE; ENCBS019XED ENCODE; ENCBS020YDI ENCODE; ENCBS021UTC ENCODE; ENCBS023JBH ENCODE; ENCBS024EHA ENCODE; ENCBS030ZIT ENCODE; ENCBS033QJG ENCODE; ENCBS034ENA ENCODE; ENCBS035IIS ENCODE; ENCBS038ZQB ENCODE; ENCBS039DPC ENCODE; ENCBS040DES ENCODE; ENCBS040EJF ENCODE; ENCBS042JDA ENCODE; ENCBS044VWV ENCODE; ENCBS045GOD ENCODE; ENCBS045OVM ENCODE; ENCBS048XFP ENCODE; ENCBS049KBY ENCODE; ENCBS049QKG ENCODE; ENCBS049RJI ENCODE; ENCBS051IBT ENCODE; ENCBS053QGR ENCODE; ENCBS055KDL ENCODE; ENCBS060DQW ENCODE; ENCBS061GZI ENCODE; ENCBS063CQL ENCODE; ENCBS063KED ENCODE; ENCBS065LQD ENCODE; ENCBS066SAB ENCODE; ENCBS066SXT ENCODE; ENCBS067QSF ENCODE; ENCBS068DNA ENCODE; ENCBS070YKP ENCODE; ENCBS072JEO ENCODE; ENCBS074GMS ENCODE; ENCBS074IZI ENCODE; ENCBS074PUV ENCODE; ENCBS074YUC ENCODE; ENCBS075HYT ENCODE; ENCBS077CZP ENCODE; ENCBS077NMC ENCODE; ENCBS085IZZ ENCODE; ENCBS086PXC ENCODE; ENCBS086XEN ENCODE; ENCBS087QWF ENCODE; ENCBS088KUZ ENCODE; ENCBS089VZP ENCODE; ENCBS093QOO ENCODE; ENCBS096XGH ENCODE; ENCBS101LFX ENCODE; ENCBS101OYY ENCODE; ENCBS103LSZ ENCODE; ENCBS104QEK ENCODE; ENCBS106DQT ENCODE; ENCBS108PEU ENCODE; ENCBS110FVC ENCODE; ENCBS111IHC ENCODE; ENCBS113GKP ENCODE; ENCBS114ENC ENCODE; ENCBS114MFP ENCODE; ENCBS116IFC ENCODE; ENCBS116LNU ENCODE; ENCBS117BTL ENCODE; ENCBS118LZR ENCODE; ENCBS120JBW ENCODE; ENCBS121IFK ENCODE; ENCBS129BNW ENCODE; ENCBS130RRG ENCODE; ENCBS132XIH ENCODE; ENCBS133GYV ENCODE; ENCBS134OGP ENCODE; ENCBS135IEJ ENCODE; ENCBS135KID ENCODE; ENCBS136HQP ENCODE; ENCBS137REJ ENCODE; ENCBS138OWD ENCODE; ENCBS142FZQ ENCODE; ENCBS143CPJ ENCODE; ENCBS143EIV ENCODE; ENCBS144MRF ENCODE; ENCBS145HYP ENCODE; ENCBS145YLE ENCODE; ENCBS147BEL ENCODE; ENCBS148AQX ENCODE; ENCBS148BFZ ENCODE; ENCBS149ZGY ENCODE; ENCBS152RQC ENCODE; ENCBS157CAN ENCODE; ENCBS158NUW ENCODE; ENCBS171TJQ ENCODE; ENCBS172NZN ENCODE; ENCBS173ACT ENCODE; ENCBS175ALJ ENCODE; ENCBS176LHZ ENCODE; ENCBS178ASF ENCODE; ENCBS180AZS ENCODE; ENCBS180QVY ENCODE; ENCBS180UZG ENCODE; ENCBS181KHF ENCODE; ENCBS183QJT ENCODE; ENCBS192GTP ENCODE; ENCBS194AMD ENCODE; ENCBS197XGU ENCODE; ENCBS199RMB ENCODE; ENCBS199ZPD ENCODE; ENCBS200OKV ENCODE; ENCBS201IDJ ENCODE; ENCBS202CLF ENCODE; ENCBS204FOO ENCODE; ENCBS204QRM ENCODE; ENCBS205JEO ENCODE; ENCBS207OWT ENCODE; ENCBS210MLW ENCODE; ENCBS210TEK ENCODE; ENCBS213GIX ENCODE; ENCBS217MRJ ENCODE; ENCBS218GVF ENCODE; ENCBS218PEV ENCODE; ENCBS221OJT ENCODE; ENCBS222ZOM ENCODE; ENCBS224CAS ENCODE; ENCBS224OGG ENCODE; ENCBS225ERF ENCODE; ENCBS226JWQ ENCODE; ENCBS230TCM ENCODE; ENCBS233NIP ENCODE; ENCBS236NEP ENCODE; ENCBS237FEL ENCODE; ENCBS237TGJ ENCODE; ENCBS239AGG ENCODE; ENCBS242YTF ENCODE; ENCBS243GXZ ENCODE; ENCBS246HTK ENCODE; ENCBS248XEV ENCODE; ENCBS250DDC ENCODE; ENCBS250EAA ENCODE; ENCBS250QAH ENCODE; ENCBS252ZVH ENCODE; ENCBS253SJT ENCODE; ENCBS257TYR ENCODE; ENCBS257WFM ENCODE; ENCBS258IBQ ENCODE; ENCBS260QIN ENCODE; ENCBS263MSZ ENCODE; ENCBS266IRW ENCODE; ENCBS269MQH ENCODE; ENCBS269TMY ENCODE; ENCBS269UBV ENCODE; ENCBS270KOG ENCODE; ENCBS271FCJ ENCODE; ENCBS275NVW ENCODE; ENCBS280KDG ENCODE; ENCBS281JZX ENCODE; ENCBS282XVK ENCODE; ENCBS285EHM ENCODE; ENCBS287NGC ENCODE; ENCBS287RQP ENCODE; ENCBS289IAE ENCODE; ENCBS292XKE ENCODE; ENCBS295BTT ENCODE; ENCBS295NFS ENCODE; ENCBS296ABO ENCODE; ENCBS296SQC ENCODE; ENCBS296VMM ENCODE; ENCBS299YGH ENCODE; ENCBS300GHC ENCODE; ENCBS300YFU ENCODE; ENCBS301IGN ENCODE; ENCBS301LDQ ENCODE; ENCBS303VDB ENCODE; ENCBS306CIA ENCODE; ENCBS307OQZ ENCODE; ENCBS308ZPA ENCODE; ENCBS310TGK ENCODE; ENCBS311FWL ENCODE; ENCBS313GMZ ENCODE; ENCBS314VPT ENCODE; ENCBS315MGA ENCODE; ENCBS315PDD ENCODE; ENCBS321SWI ENCODE; ENCBS322SEN ENCODE; ENCBS335TOC ENCODE; ENCBS336RRO ENCODE; ENCBS337HXQ ENCODE; ENCBS337WWP ENCODE; ENCBS338VUB ENCODE; ENCBS339GWD ENCODE; ENCBS339SIT ENCODE; ENCBS341ITG ENCODE; ENCBS342VWN ENCODE; ENCBS344JWL ENCODE; ENCBS344VFK ENCODE; ENCBS346DEZ ENCODE; ENCBS346EFV ENCODE; ENCBS349HZS ENCODE; ENCBS351JCJ ENCODE; ENCBS352ZNU ENCODE; ENCBS354PIF ENCODE; ENCBS354ZLY ENCODE; ENCBS356MOV ENCODE; ENCBS357UNN ENCODE; ENCBS358XLG ENCODE; ENCBS362ASG ENCODE; ENCBS363GXU ENCODE; ENCBS375JNA ENCODE; ENCBS380ZOW ENCODE; ENCBS381BBR ENCODE; ENCBS385LUB ENCODE; ENCBS399FDJ ENCODE; ENCBS399GAF ENCODE; ENCBS400CWC ENCODE; ENCBS401LBP ENCODE; ENCBS402BUA ENCODE; ENCBS402VZL ENCODE; ENCBS403UGF ENCODE; ENCBS404EOZ ENCODE; ENCBS405FLI ENCODE; ENCBS405JBR ENCODE; ENCBS408JNN ENCODE; ENCBS409RQS ENCODE; ENCBS413HHW ENCODE; ENCBS415VLW ENCODE; ENCBS416YET ENCODE; ENCBS421OZB ENCODE; ENCBS422FYC ENCODE; ENCBS425CUD ENCODE; ENCBS429YJD ENCODE; ENCBS430PSA ENCODE; ENCBS431NPJ ENCODE; ENCBS433CTJ ENCODE; ENCBS433TIQ ENCODE; ENCBS433UJJ ENCODE; ENCBS435MPV ENCODE; ENCBS435NIB ENCODE; ENCBS437UIO ENCODE; ENCBS440GZN ENCODE; ENCBS441XTP ENCODE; ENCBS443JPP ENCODE; ENCBS444QIJ ENCODE; ENCBS446KHP ENCODE; ENCBS447JNO ENCODE; ENCBS449AIA ENCODE; ENCBS449LCQ ENCODE; ENCBS453TYZ ENCODE; ENCBS455OVD ENCODE; ENCBS456NEZ ENCODE; ENCBS464VEI ENCODE; ENCBS465DEI ENCODE; ENCBS466PDL ENCODE; ENCBS467XVF ENCODE; ENCBS470TSC ENCODE; ENCBS470XDJ ENCODE; ENCBS471DUZ ENCODE; ENCBS471EIZ ENCODE; ENCBS472BZM ENCODE; ENCBS474AND ENCODE; ENCBS475AHQ ENCODE; ENCBS476TPW ENCODE; ENCBS479RLA ENCODE; ENCBS481IVE ENCODE; ENCBS483WGW ENCODE; ENCBS484TBT ENCODE; ENCBS485OKN ENCODE; ENCBS486CUL ENCODE; ENCBS487KTY ENCODE; ENCBS487SZV ENCODE; ENCBS488HLS ENCODE; ENCBS488UTE ENCODE; ENCBS489ZQI ENCODE; ENCBS492SDY ENCODE; ENCBS501AJE ENCODE; ENCBS501FGJ ENCODE; ENCBS502APU ENCODE; ENCBS502FPQ ENCODE; ENCBS503ZYE ENCODE; ENCBS504IUW ENCODE; ENCBS504VHS ENCODE; ENCBS505LMC ENCODE; ENCBS506FKT ENCODE; ENCBS508YFO ENCODE; ENCBS511ZQV ENCODE; ENCBS515IJA ENCODE; ENCBS515KFV ENCODE; ENCBS520MGH ENCODE; ENCBS522AAA ENCODE; ENCBS523AAA ENCODE; ENCBS524YUI ENCODE; ENCBS525TLA ENCODE; ENCBS530ENF ENCODE; ENCBS530LIV ENCODE; ENCBS530VUT ENCODE; ENCBS531RMF ENCODE; ENCBS533IVT ENCODE; ENCBS537ADD ENCODE; ENCBS540JSU ENCODE; ENCBS541YFT ENCODE; ENCBS542DRS ENCODE; ENCBS542YDW ENCODE; ENCBS544ETZ ENCODE; ENCBS544WQP ENCODE; ENCBS546FZO ENCODE; ENCBS547FPL ENCODE; ENCBS547JWV ENCODE; ENCBS548DDM ENCODE; ENCBS548DJV ENCODE; ENCBS550FNB ENCODE; ENCBS550RQC ENCODE; ENCBS551CUU ENCODE; ENCBS551DVZ ENCODE; ENCBS551QFT ENCODE; ENCBS553PEJ ENCODE; ENCBS554TEZ ENCODE; ENCBS555BYF ENCODE; ENCBS555IZN ENCODE; ENCBS557NDG ENCODE; ENCBS560TQP ENCODE; ENCBS562WFV ENCODE; ENCBS571XTM ENCODE; ENCBS573EMA ENCODE; ENCBS573OLZ ENCODE; ENCBS574ZRE ENCODE; ENCBS575HTN ENCODE; ENCBS579HCA ENCODE; ENCBS581BGT ENCODE; ENCBS582KNJ ENCODE; ENCBS582REX ENCODE; ENCBS590WTW ENCODE; ENCBS591PPP ENCODE; ENCBS595FPT ENCODE; ENCBS598VSF ENCODE; ENCBS599QJL ENCODE; ENCBS600ITX ENCODE; ENCBS607IVB ENCODE; ENCBS608AFV ENCODE; ENCBS608OON ENCODE; ENCBS610IGG ENCODE; ENCBS610UML ENCODE; ENCBS611LWG ENCODE; ENCBS611PFD ENCODE; ENCBS611WLI ENCODE; ENCBS612GBT ENCODE; ENCBS614CMA ENCODE; ENCBS619OWS ENCODE; ENCBS621TAB ENCODE; ENCBS623BZF ENCODE; ENCBS624DUS ENCODE; ENCBS624MLL ENCODE; ENCBS626BOT ENCODE; ENCBS628IQK ENCODE; ENCBS628MMK ENCODE; ENCBS634THO ENCODE; ENCBS635NSH ENCODE; ENCBS636ANV ENCODE; ENCBS637UJM ENCODE; ENCBS638AAA ENCODE; ENCBS638ASL ENCODE; ENCBS638MWB ENCODE; ENCBS641AVI ENCODE; ENCBS644PWW ENCODE; ENCBS644SVK ENCODE; ENCBS645YGY ENCODE; ENCBS646RDV ENCODE; ENCBS648DPW ENCODE; ENCBS650CRD ENCODE; ENCBS650SLE ENCODE; ENCBS656AXT ENCODE; ENCBS662HXP ENCODE; ENCBS664KGZ ENCODE; ENCBS664MRR ENCODE; ENCBS665IBY ENCODE; ENCBS665LZL ENCODE; ENCBS668RFG ENCODE; ENCBS669DWT ENCODE; ENCBS670FFG ENCODE; ENCBS671AAA ENCODE; ENCBS671WOF ENCODE; ENCBS672AAA ENCODE; ENCBS672UJA ENCODE; ENCBS673AAA ENCODE; ENCBS674AAA ENCODE; ENCBS675AAA ENCODE; ENCBS676AAA ENCODE; ENCBS680YLF ENCODE; ENCBS684ULB ENCODE; ENCBS686ZOG ENCODE; ENCBS689DEE ENCODE; ENCBS692BSS ENCODE; ENCBS692HLB ENCODE; ENCBS694IAG ENCODE; ENCBS696KRJ ENCODE; ENCBS696RMN ENCODE; ENCBS697FZF ENCODE; ENCBS697NJJ ENCODE; ENCBS699OCX ENCODE; ENCBS702HBU ENCODE; ENCBS702PRB ENCODE; ENCBS704AVG ENCODE; ENCBS704TEF ENCODE; ENCBS705HMQ ENCODE; ENCBS705NHL ENCODE; ENCBS706BWK ENCODE; ENCBS712AAA ENCODE; ENCBS713BFI ENCODE; ENCBS713IGS ENCODE; ENCBS715MWV ENCODE; ENCBS715WYI ENCODE; ENCBS716VBH ENCODE; ENCBS716YFX ENCODE; ENCBS718VVA ENCODE; ENCBS719OUD ENCODE; ENCBS720SBS ENCODE; ENCBS721RXI ENCODE; ENCBS722LIJ ENCODE; ENCBS722TNF ENCODE; ENCBS727GLB ENCODE; ENCBS727VRH ENCODE; ENCBS729TZG ENCODE; ENCBS730DQI ENCODE; ENCBS731WFK ENCODE; ENCBS732KTS ENCODE; ENCBS734JXY ENCODE; ENCBS734KAG ENCODE; ENCBS738ADY ENCODE; ENCBS739HLB ENCODE; ENCBS740FAU ENCODE; ENCBS740NNE ENCODE; ENCBS740QWK ENCODE; ENCBS741AAA ENCODE; ENCBS741RGH ENCODE; ENCBS741YEQ ENCODE; ENCBS742AAA ENCODE; ENCBS743AAA ENCODE; ENCBS743JKX ENCODE; ENCBS743RUU ENCODE; ENCBS743ZMW ENCODE; ENCBS744AAA ENCODE; ENCBS745AAA ENCODE; ENCBS745AQT ENCODE; ENCBS745UGC ENCODE; ENCBS746AAA ENCODE; ENCBS748YQE ENCODE; ENCBS751GYX ENCODE; ENCBS753KCK ENCODE; ENCBS754KRB ENCODE; ENCBS755JGR ENCODE; ENCBS755NZH ENCODE; ENCBS756FJO ENCODE; ENCBS757QFO ENCODE; ENCBS762HAX ENCODE; ENCBS763BBP ENCODE; ENCBS765FVI ENCODE; ENCBS767KUR ENCODE; ENCBS767MPH ENCODE; ENCBS768ZGL ENCODE; ENCBS771QGO ENCODE; ENCBS773AAA ENCODE; ENCBS774QLP ENCODE; ENCBS775MDU ENCODE; ENCBS775NGD ENCODE; ENCBS775RGP ENCODE; ENCBS777STD ENCODE; ENCBS777UEV ENCODE; ENCBS778JAH ENCODE; ENCBS778LCM ENCODE; ENCBS779XEH ENCODE; ENCBS780BKX ENCODE; ENCBS781BOJ ENCODE; ENCBS782BXQ ENCODE; ENCBS783AYY ENCODE; ENCBS783PVI ENCODE; ENCBS783YSP ENCODE; ENCBS786WUO ENCODE; ENCBS787BXG ENCODE; ENCBS789ZNN ENCODE; ENCBS791ETZ ENCODE; ENCBS791FZV ENCODE; ENCBS793GXQ ENCODE; ENCBS798HNT ENCODE; ENCBS798MOH ENCODE; ENCBS798PZJ ENCODE; ENCBS799LNH ENCODE; ENCBS799SQC ENCODE; ENCBS800QIW ENCODE; ENCBS803IPJ ENCODE; ENCBS803ZJJ ENCODE; ENCBS805UZF ENCODE; ENCBS806AAA ENCODE; ENCBS807AAA ENCODE; ENCBS809KDQ ENCODE; ENCBS810BDN ENCODE; ENCBS810JOY ENCODE; ENCBS811GQK ENCODE; ENCBS811PND ENCODE; ENCBS813FSC ENCODE; ENCBS814VTY ENCODE; ENCBS815MFP ENCODE; ENCBS816PYX ENCODE; ENCBS817DXX ENCODE; ENCBS817NZJ ENCODE; ENCBS818CDN ENCODE; ENCBS821PLV ENCODE; ENCBS824AAA ENCODE; ENCBS824QCP ENCODE; ENCBS825AAA ENCODE; ENCBS826AAA ENCODE; ENCBS827QKB ENCODE; ENCBS832ULV ENCODE; ENCBS835AAA ENCODE; ENCBS835EOX ENCODE; ENCBS835UPQ ENCODE; ENCBS836AAA ENCODE; ENCBS836LJE ENCODE; ENCBS837AAA ENCODE; ENCBS839SGI ENCODE; ENCBS840QTY ENCODE; ENCBS842MLZ ENCODE; ENCBS844EBE ENCODE; ENCBS847PBZ ENCODE; ENCBS848AAA ENCODE; ENCBS849AAA ENCODE; ENCBS849LND ENCODE; ENCBS850PLY ENCODE; ENCBS851ZNE ENCODE; ENCBS853NQW ENCODE; ENCBS854HTL ENCODE; ENCBS856GWK ENCODE; ENCBS857THE ENCODE; ENCBS858AAA ENCODE; ENCBS859AAA ENCODE; ENCBS859FFE ENCODE; ENCBS859RAZ ENCODE; ENCBS860AAA ENCODE; ENCBS861HMN ENCODE; ENCBS862LXP ENCODE; ENCBS863WKZ ENCODE; ENCBS864WAF ENCODE; ENCBS864XFG ENCODE; ENCBS866LUZ ENCODE; ENCBS868JIC ENCODE; ENCBS869GQP ENCODE; ENCBS870TBE ENCODE; ENCBS872GDG ENCODE; ENCBS873PJJ ENCODE; ENCBS875LKB ENCODE; ENCBS877GRH ENCODE; ENCBS877WFF ENCODE; ENCBS879GXJ ENCODE; ENCBS879MRD ENCODE; ENCBS881CIF ENCODE; ENCBS882YXM ENCODE; ENCBS883DWI ENCODE; ENCBS885FSX ENCODE; ENCBS885JQS ENCODE; ENCBS885ORM ENCODE; ENCBS887RIJ ENCODE; ENCBS892VZB ENCODE; ENCBS895EOS ENCODE; ENCBS895HRB ENCODE; ENCBS896YYX ENCODE; ENCBS897BFW ENCODE; ENCBS897HQV ENCODE; ENCBS899ZNE ENCODE; ENCBS900XSC ENCODE; ENCBS901YOY ENCODE; ENCBS902IAH ENCODE; ENCBS904EKE ENCODE; ENCBS905ULQ ENCODE; ENCBS907KSW ENCODE; ENCBS909PJP ENCODE; ENCBS910PZQ ENCODE; ENCBS910ZFQ ENCODE; ENCBS912TCF ENCODE; ENCBS913KLP ENCODE; ENCBS914FGT ENCODE; ENCBS918RGX ENCODE; ENCBS923MFQ ENCODE; ENCBS924KDO ENCODE; ENCBS924WYL ENCODE; ENCBS927AKA ENCODE; ENCBS928CHW ENCODE; ENCBS930FIG ENCODE; ENCBS931EXY ENCODE; ENCBS931SHZ ENCODE; ENCBS937BJO ENCODE; ENCBS937LVM ENCODE; ENCBS939AYV ENCODE; ENCBS943ASZ ENCODE; ENCBS948WDK ENCODE; ENCBS949DPY ENCODE; ENCBS949YDI ENCODE; ENCBS950MSQ ENCODE; ENCBS955ZHF ENCODE; ENCBS956FFN ENCODE; ENCBS959DVN ENCODE; ENCBS961ZJH ENCODE; ENCBS962POD ENCODE; ENCBS967NRV ENCODE; ENCBS967UNG ENCODE; ENCBS967WNR ENCODE; ENCBS970EPG ENCODE; ENCBS974ELC ENCODE; ENCBS976OQX ENCODE; ENCBS976TOE ENCODE; ENCBS976ZOG ENCODE; ENCBS978CGB ENCODE; ENCBS983ECZ ENCODE; ENCBS983YXQ ENCODE; ENCBS984EPA ENCODE; ENCBS985FRY ENCODE; ENCBS985WFY ENCODE; ENCBS985WNX ENCODE; ENCBS987BVJ ENCODE; ENCBS987KVB ENCODE; ENCBS990SBY ENCODE; ENCBS991MPK ENCODE; ENCBS992ZRR ENCODE; ENCBS994TMS ENCODE; ENCBS994VIY ENCODE; ENCBS995NXW ENCODE; ENCBS995WFW ENCODE; ENCBS998QYV GEO; GSM207049 GEO; GSM472906 GEO; GSM472907 GEO; GSM481450 GEO; GSM501780 GEO; GSM565883 GEO; GSM733638 GEO; GSM733641 GEO; GSM733645 GEO; GSM733685 GEO; GSM733693 GEO; GSM733694 GEO; GSM733737 GEO; GSM733743 GEO; GSM733754 GEO; GSM733774 GEO; GSM736637 GEO; GSM736639 GEO; GSM749683 GEO; GSM749715 GEO; GSM782122 GEO; GSM798321 GEO; GSM803336 GEO; GSM803343 GEO; GSM803344 GEO; GSM803367 GEO; GSM803368 GEO; GSM803381 GEO; GSM803403 GEO; GSM803404 GEO; GSM803415 GEO; GSM803418 GEO; GSM803432 GEO; GSM803449 GEO; GSM803451 GEO; GSM803452 GEO; GSM803460 GEO; GSM803461 GEO; GSM803483 GEO; GSM803486 GEO; GSM803493 GEO; GSM803499 GEO; GSM803500 GEO; GSM803502 GEO; GSM803503 GEO; GSM803507 GEO; GSM803517 GEO; GSM803527 GEO; GSM803530 GEO; GSM816662 GEO; GSM822284 GEO; GSM822287 GEO; GSM822291 GEO; GSM887079 GEO; GSM888149 GEO; GSM923446 GEO; GSM935274 GEO; GSM935275 GEO; GSM935280 GEO; GSM935304 GEO; GSM935305 GEO; GSM935306 GEO; GSM935307 GEO; GSM935335 GEO; GSM935350 GEO; GSM935364 GEO; GSM935406 GEO; GSM935437 GEO; GSM935493 GEO; GSM935542 GEO; GSM935543 GEO; GSM935545 GEO; GSM935566 GEO; GSM935579 GEO; GSM935596 GEO; GSM935603 GEO; GSM935609 GEO; GSM935610 GEO; GSM935646 GEO; GSM935647 GEO; GSM935648 GEO; GSM935649 GEO; GSM935650 GEO; GSM936760 GEO; GSM945182 GEO; GSM945211 GEO; GSM945231 GEO; GSM945291 GEO; GSM1003487 GEO; GSM1003519 GEO; GSM1010740 GEO; GSM1010741 GEO; GSM1010777 GEO; GSM1010778 GEO; GSM1010784 GEO; GSM1010787 GEO; GSM1010808 GEO; GSM1010809 GEO; GSM1010810 GEO; GSM1010821 GEO; GSM1010831 GEO; GSM1010865 GEO; GSM1010875 GEO; GSM1010876 GEO; GSM1040305 GEO; GSM1040375 GEO; GSM1374138 GEO; GSM1374139 GEO; GSM1374140 GEO; GSM1374141 GEO; GSM1374142 GEO; GSM1374143 GEO; GSM1374144 GEO; GSM1374145 GEO; GSM1374146 GEO; GSM1374147 GEO; GSM1374148 GEO; GSM1374532 GEO; GSM1669878 IBRC; C10096 ICLC; HTL95005 IGRhCellID; HepG2 IZSLER; BS TCL 79 JCRB; JCRB1054 JCRB; NIHS0326 KCB; KCB 200507YJ KCLB; 88065 LiGeA; CCLE_410 LINCS_LDP; LCL-1925 Lonza; 62 MetaboLights; MTBLS127 MetaboLights; MTBLS419 MetaboLights; MTBLS582 NCBI_Iran; C158 PRIDE; PXD000661 PRIDE; PXD001874 PRIDE; PXD002395 PRIDE; PXD003370 PRIDE; PXD004252 PRIDE; PXD005955 PRIDE; PXD008190 RCB; RCB0459 RCB; RCB1648 RCB; RCB1886 TKG; TKG 0205 TOKU-E; 1440 Wikidata; Q5731621 DT Created: 04-04-12; Last updated: 05-07-19; Version: 30

Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes.

  • Qin XY
  • EBioMedicine
  • 2018 Jun 18

Literature context:


Abstract:

The acute phase protein orosomucoid-1 (Orm1) is mainly expressed by hepatocytes (HPCs) under stress conditions. However, its specific function is not fully understood. Here, we report a role of Orm1 as an executer of HPC proliferation. Increases in serum levels of Orm1 were observed in patients after surgical resection for liver cancer and in mice undergone partial hepatectomy (PH). Transcriptome study showed that Orm1 became the most abundant in HPCs isolated from regenerating mouse liver tissues after PH. Both in vitro and in vivo siRNA-induced knockdown of Orm1 suppressed proliferation of mouse regenerating HPCs and human hepatic cells. Microarray analysis in regenerating mouse livers revealed that the signaling pathways controlling chromatin replication, especially the minichromosome maintenance protein complex genes were uniformly down-regulated following Orm1 knockdown. These data suggest that Orm1 is induced in response to hepatic injury and executes liver regeneration by activating cell cycle progression in HPCs.

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.

  • Kim KH
  • Cell Metab.
  • 2018 Jun 27

Literature context:


Abstract:

Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated.

Funding information:
  • NIDDK NIH HHS - DK074310(United States)

Time-dependent expression pattern of cytochrome P450 epoxygenases and soluble epoxide hydrolase in normal human placenta.

  • Cizkova K
  • Acta Histochem.
  • 2018 Jun 13

Literature context:


Abstract:

CYP2C and CYP2 J enzymes, commonly named as cytochrome P450 (CYP) epoxygenases, convert arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), biologically active eicosanoids with many functions in organism. EETs are rapidly hydrolysed to less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We investigated spatio-temporal expression pattern of CYP2C8, CYP2C9, CYP2 J2 and sEH in normal human placenta by immunohistochemical method. In the villous trophoblast, CYP2C8 was the most abundant protein. Its expression is higher than the CYP2C9 and CYP2 J2 in the cytotrophoblast in the embryonic stage of development and remains higher in syncytiotrophoblast of term placenta. Unlike to CYP2C8, CYP2C9 and CYP2 J2 expression decrease in term placenta. sEH expression increases with gestation age and is strictly limited to cytotrophoblast in embryonic and foetal stages of the development. Moreover, CYP2C8 shows more intensive staining than the other protein monitored in Hofbauer cells in villous stroma. Specific information regarding the exact role of EETs and DHETs functions in a normal placenta is still unknown. Based on CYP epoxygenases and sEH localization and well known information about the functions of placental structures during development, we suggest that these enzymes could play different roles in various cell populations in the placenta. As the placenta is absolutely crucial for prenatal development, arachidonic acid is essential part of human nutrient and CYP epoxygenases expression can be affected by xenobiotics, further investigation of the exact role of CYP epoxygenases, sEH, and their metabolites in normal pregnancy and under pathological conditions is needed.

Funding information:
  • Biotechnology and Biological Sciences Research Council - BB/I003142/1(United Kingdom)

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.

  • Qian M
  • Elife
  • 2018 May 2

Literature context:


Abstract:

DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.

Funding information:
  • Department of Health - (United Kingdom)
  • Ministry of Science and Technology of the People's Republic of China - 2016YFC0904600()
  • Ministry of Science and Technology of the People's Republic of China - 2017YFA0503900()
  • National Natural Science Foundation of China - 81422016()
  • National Natural Science Foundation of China - 81501206()
  • National Natural Science Foundation of China - 81501210()
  • National Natural Science Foundation of China - 81571374()
  • National Natural Science Foundation of China - 91439133()
  • Natural Science Foundation of Guangdong Province - 2014A030308011()
  • Natural Science Foundation of Guangdong Province - 2015A030308007()
  • Natural Science Foundation of Guangdong Province - 2016A030310064()
  • Research Grant Council of Hong Kong - 773313()
  • Research Grant Council of Hong Kong - HKU2/CRF/13G()
  • Shenzhen Science and Technology Innovation Commission - CXZZ20140903103747568()
  • Shenzhen Science and Technology Innovation Commission - JCYJ20140418095735645()
  • Shenzhen Science and Technology Innovation Commission - JCYJ20160226191451487()

De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry.

  • Passioura T
  • Cell Chem Biol
  • 2018 May 2

Literature context:


Abstract:

Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-standard peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addition to their anti-HBV activity, these molecules also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clinically relevant nucleos(t)ide analog-resistant and vaccine escaping strains). Importantly, these macrocyclic peptides, in contrast to other NTCP-binding HBV entry inhibitors, exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.

Funding information:
  • Division of Molecular and Cellular Biosciences - MCB-1121334()
  • NCI NIH HHS - 1R21CA141009(United States)

Systematic Discovery of RNA Binding Proteins that Regulate MicroRNA Levels.

  • Nussbacher JK
  • Mol. Cell
  • 2018 Mar 15

Literature context:


Abstract:

RNA binding proteins (RBPs) interact with primary, precursor, and mature microRNAs (miRs) to influence mature miR levels, which in turn affect critical aspects of human development and disease. To understand how RBPs contribute to miR biogenesis, we analyzed human enhanced UV crosslinking followed by immunoprecipitation (eCLIP) datasets for 126 RBPs to discover miR-encoding genomic loci that are statistically enriched for RBP binding. We find that 92% of RBPs interact directly with at least one miR locus, and that some interactions are cell line specific despite expression of the miR locus in both cell lines evaluated. We validated that ILF3 and BUD13 directly interact with and stabilize miR-144 and that BUD13 suppresses mir-210 processing to the mature species. We also observed that DDX3X regulates primary miR-20a, while LARP4 stabilizes precursor mir-210. Our approach to identifying regulators of miR loci can be applied to any user-defined RNA annotation, thereby guiding the discovery of uncharacterized regulators of RNA processing.

Funding information:
  • Howard Hughes Medical Institute - 5T32GM007454(United States)

LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia.

  • Tarumoto Y
  • Mol. Cell
  • 2018 Mar 15

Literature context:


Abstract:

The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. We also found that MEF2C-dependent leukemias are sensitive to on-target chemical inhibition of SIK activity. This study reveals a chemical strategy to block MEF2C function in AML, highlighting how an oncogenic TF can be disabled by targeting of upstream kinases.

Funding information:
  • NCI NIH HHS - P01 CA013106()
  • NCI NIH HHS - R01 CA174793()
  • NIDDK NIH HHS - DK64540(United States)

Transcriptional Regulation of the Warburg Effect in Cancer by SIX1.

  • Li L
  • Cancer Cell
  • 2018 Mar 12

Literature context:


Abstract:

Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.

Funding information:
  • NHLBI NIH HHS - HL084312(United States)

Differential Expression of NF2 in Neuroepithelial Compartments Is Necessary for Mammalian Eye Development.

  • Moon KH
  • Dev. Cell
  • 2018 Jan 8

Literature context:


Abstract:

The optic neuroepithelial continuum of vertebrate eye develops into three differentially growing compartments: the retina, the ciliary margin (CM), and the retinal pigment epithelium (RPE). Neurofibromin 2 (Nf2) is strongly expressed in slowly expanding RPE and CM compartments, and the loss of mouse Nf2 causes hyperplasia in these compartments, replicating the ocular abnormalities seen in human NF2 patients. The hyperplastic ocular phenotypes were largely suppressed by heterozygous deletion of Yap and Taz, key targets of the Nf2-Hippo signaling pathway. We also found that, in addition to feedback transcriptional regulation of Nf2 by Yap/Taz in the CM, activation of Nf2 expression by Mitf in the RPE and suppression by Sox2 in retinal progenitor cells are necessary for the differential growth of the corresponding cell populations. Together, our findings reveal that Nf2 is a key player that orchestrates the differential growth of optic neuroepithelial compartments during vertebrate eye development.

Funding information:
  • NEI NIH HHS - R01 EY013760()
  • NIAMS NIH HHS - R01 AR050772-09(United States)

Systems Pharmacology Dissection of Cholesterol Regulation Reveals Determinants of Large Pharmacodynamic Variability between Cell Lines.

  • Blattmann P
  • Cell Syst
  • 2017 Dec 27

Literature context:


Abstract:

In individuals, heterogeneous drug-response phenotypes result from a complex interplay of dose, drug specificity, genetic background, and environmental factors, thus challenging our understanding of the underlying processes and optimal use of drugs in the clinical setting. Here, we use mass-spectrometry-based quantification of molecular response phenotypes and logic modeling to explain drug-response differences in a panel of cell lines. We apply this approach to cellular cholesterol regulation, a biological process with high clinical relevance. From the quantified molecular phenotypes elicited by various targeted pharmacologic or genetic treatments, we generated cell-line-specific models that quantified the processes beneath the idiotypic intracellular drug responses. The models revealed that, in addition to drug uptake and metabolism, further cellular processes displayed significant pharmacodynamic response variability between the cell lines, resulting in cell-line-specific drug-response phenotypes. This study demonstrates the importance of integrating different types of quantitative systems-level molecular measurements with modeling to understand the effect of pharmacological perturbations on complex biological processes.

Funding information:
  • NCI NIH HHS - 5 P30 CA46592(United States)

An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3.

  • Kizuka Y
  • Cell Chem Biol
  • 2017 Dec 21

Literature context:


Abstract:

Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-Alk-Fuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc). The action mechanism was shown to deplete cellular GDP-Fuc, and the direct target of 6-Alk-Fuc is FX (encoded by TSTA3), the bifunctional GDP-Fuc synthase. We also show that 6-Alk-Fuc halts hepatoma invasion. These results highlight the unappreciated role of 6-Alk-Fuc as a fucosylation inhibitor and its potential use for basic and clinical science.

Funding information:
  • NIGMS NIH HHS - GM068763(United States)

Boron-Based Inhibitors of the NLRP3 Inflammasome.

  • Baldwin AG
  • Cell Chem Biol
  • 2017 Nov 16

Literature context:


Abstract:

NLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.

TGF-β signalling and PEG10 are mutually exclusive and inhibitory in chondrosarcoma cells.

  • Shinohara N
  • Sci Rep
  • 2017 Oct 18

Literature context:


Abstract:

Histological distinction between enchondroma and chondrosarcoma is difficult because of a lack of definitive biomarkers. Here, we found highly active transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling in human chondrosarcomas compared with enchondromas by immunohistochemistry of phosphorylated SMAD3 and SMAD1/5. In contrast, the chondrogenic master regulator SOX9 was dramatically down-regulated in grade 1 chondrosarcoma. Paternally expressed gene 10 (PEG10) was identified by microarray analysis as a gene overexpressed in chondrosarcoma SW1353 and Hs 819.T cells compared with C28/I2 normal chondrocytes, while TGF-β1 treatment, mimicking higher grade tumour conditions, suppressed PEG10 expression. Enchondroma samples exhibited stronger expression of PEG10 compared with chondrosarcomas, suggesting a negative association of PEG10 with malignant cartilage tumours. In chondrosarcoma cell lines, application of the TGF-β signalling inhibitor, SB431542, increased the protein level of PEG10. Reporter assays revealed that PEG10 repressed TGF-β and BMP signalling, which are both SMAD pathways, whereas PEG10 knockdown increased the level of phosphorylated SMAD3 and SMAD1/5/9. Our results indicate that mutually exclusive expression of PEG10 and phosphorylated SMADs in combination with differentially expressed SOX9 is an index to distinguish between enchondroma and chondrosarcoma, while PEG10 and TGF-β signalling are mutually inhibitory in chondrosarcoma cells.

Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals.

  • Xu J
  • Cell Death Dis
  • 2017 Oct 12

Literature context:


Abstract:

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.

Impact of intracellular glyceraldehyde-derived advanced glycation end-products on human hepatocyte cell death.

  • Sakasai-Sakai A
  • Sci Rep
  • 2017 Oct 27

Literature context:


Abstract:

Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH); however, the pathogenesis of NASH currently remains unclear. We aimed to investigate the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (GA-AGEs) on human hepatocyte cell death. The accumulation of intracellular GA-AGEs has been associated with the induction of DNA damage and hepatocyte necrotic cell death. Among intracellular GA-AGEs, caspase-3 has been identified as a GA-AGE-modified protein with abrogated protein function. Furthermore, the activation of caspase-3 and induction of hepatocyte apoptosis by camptothecin, a DNA-damaging agent, was suppressed by a treatment with GA. These results suggest the inhibitory effects of GA-AGE-modified caspase-3 on the induction of DNA-damage-induced apoptosis, which is associated with hepatocyte necrosis. Therefore, the suppression of necrosis, the inflammatory form of cell death, by the accumulation of GA-AGEs and GA-AGE-modified caspase-3 may represent a novel therapeutic target for the pathogenesis of NASH.

Survival Motor Neuron Protein is Released from Cells in Exosomes: A Potential Biomarker for Spinal Muscular Atrophy.

  • Nash LA
  • Sci Rep
  • 2017 Oct 24

Literature context:


Abstract:

Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of SMA released exosomes containing reduced levels of SMN protein relative to normal controls. Cells overexpressing SMN protein released exosomes with dramatically elevated levels of SMN protein. We observed enhanced quantities of exosomes in the medium from SMN-depleted cells, and in serum from a mouse model of SMA and a patient with Type 3 SMA, suggesting that SMN-depletion causes a deregulation of exosome release or uptake. The quantity of SMN protein contained in the serum-derived exosomes correlated with the genotype of the animal, with progressively less protein in carrier and affected animals compared to wildtype mice. SMN protein was easily detectable in exosomes isolated from human serum, with a reduction in the amount of SMN protein in exosomes from a patient with Type 3 SMA compared to a normal control. Our results suggest that exosome-derived SMN protein may serve as an effective biomarker for SMA.

Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma.

  • Hayashi T
  • Cancer Cell Int.
  • 2017 Oct 28

Literature context:


Abstract:

BACKGROUND: The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive (EpCAM+) CSCs. METHODS: Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. RESULTS: Whole exome sequencing on the sorted EpCAM+ and EpCAM- HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted EpCAM+ cells than in EpCAM- cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted EpCAM+ and EpCAM- cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. CONCLUSIONS: Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs.

Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover.

  • Kirsch N
  • Dev. Cell
  • 2017 Oct 9

Literature context:


Abstract:

Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

  • Trabanelli S
  • Nat Commun
  • 2017 Sep 19

Literature context:


Abstract:

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

A potent human neutralizing antibody Fc-dependently reduces established HBV infections.

  • Li D
  • Elife
  • 2017 Sep 26

Literature context:


Abstract:

Hepatitis B virus (HBV) infection is a major global health problem. Currently-available therapies are ineffective in curing chronic HBV infection. HBV and its satellite hepatitis D virus (HDV) infect hepatocytes via binding of the preS1 domain of its large envelope protein to sodium taurocholate cotransporting polypeptide (NTCP). Here, we developed novel human monoclonal antibodies that block the engagement of preS1 with NTCP and neutralize HBV and HDV with high potency. One antibody, 2H5-A14, functions at picomolar level and exhibited neutralization-activity-mediated prophylactic effects. It also acts therapeutically by eliciting antibody-Fc-dependent immunological effector functions that impose durable suppression of viral infection in HBV-infected mice, resulting in reductions in the levels of the small envelope antigen and viral DNA, with no emergence of escape mutants. Our results illustrate a novel antibody-Fc-dependent approach for HBV treatment and suggest 2H5-A14 as a novel clinical candidate for HBV prevention and treatment of chronic HBV infection.

Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism.

  • Liao W
  • Sci Rep
  • 2017 Aug 21

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Abstract:

TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

The packing density of a supramolecular membrane protein cluster is controlled by cytoplasmic interactions.

  • Merklinger E
  • Elife
  • 2017 Jul 19

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Abstract:

Molecule clustering is an important mechanism underlying cellular self-organization. In the cell membrane, a variety of fundamentally different mechanisms drive membrane protein clustering into nanometre-sized assemblies. To date, it is unknown whether this clustering process can be dissected into steps differentially regulated by independent mechanisms. Using clustered syntaxin molecules as an example, we study the influence of a cytoplasmic protein domain on the clustering behaviour. Analysing protein mobility, cluster size and accessibility to myc-epitopes we show that forces acting on the transmembrane segment produce loose clusters, while cytoplasmic protein interactions mediate a tightly packed state. We conclude that the data identify a hierarchy in membrane protein clustering likely being a paradigm for many cellular self-organization processes.

MLKL, the Protein that Mediates Necroptosis, Also Regulates Endosomal Trafficking and Extracellular Vesicle Generation.

  • Yoon S
  • Immunity
  • 2017 Jul 18

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Abstract:

Activation of the pseudokinase mixed lineage kinase domain-like (MLKL) upon its phosphorylation by the protein kinase RIPK3 triggers necroptosis, a form of programmed cell death in which rupture of cellular membranes yields release of intracellular components. We report that MLKL also associated with endosomes and controlled the transport of endocytosed proteins, thereby enhancing degradation of receptors and ligands, modulating their induced signaling and facilitating the generation of extracellular vesicles. This role was exerted on two quantitative grades: a constitutive one independent of RIPK3, and an enhanced one, triggered by RIPK3, where the association of MLKL with the endosomes was enhanced, and it was found to bind endosomal sorting complexes required for transport (ESCRT) proteins and the flotillins and to be excluded, together with them, from cells within vesicles. We suggest that release of phosphorylated MLKL within extracellular vesicles serves as a mechanism for self-restricting the necroptotic activity of this protein.

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.

  • Yuan D
  • Cancer Cell
  • 2017 Jun 12

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Abstract:

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Funding information:
  • NIDDK NIH HHS - R01 DK107220()

Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses.

  • Liu S
  • Cell Host Microbe
  • 2017 Jun 14

Literature context:


Abstract:

Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance were substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish. Small-molecule inhibitors of SFKs, which are conventional anti-tumor therapeutics, enhanced antiviral responses and protected zebrafish and mice from viral attack. Viral infection induced the expression of Lck/Hck/Fgr through TBK1-mediated mobilization of IRF3, thus constituting a negative feedback loop. These findings unveil the negative regulation of TBK1 via tyrosine phosphorylation and the functional integration of SFKs into innate antiviral immunity.

Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2.

  • Zhang S
  • Cancer Cell
  • 2017 May 8

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Abstract:

Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.

A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis.

  • Treiber T
  • Mol. Cell
  • 2017 Apr 20

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Abstract:

During microRNA (miRNA) biogenesis, two endonucleolytic reactions convert stem-loop-structured precursors into mature miRNAs. These processing steps can be posttranscriptionally regulated by RNA-binding proteins (RBPs). Here, we have used a proteomics-based pull-down approach to map and characterize the interactome of a multitude of pre-miRNAs. We identify ∼180 RBPs that interact specifically with distinct pre-miRNAs. For functional validation, we combined RNAi and CRISPR/Cas-mediated knockout experiments to analyze RBP-dependent changes in miRNA levels. Indeed, a large number of the investigated candidates, including splicing factors and other mRNA processing proteins, have effects on miRNA processing. As an example, we show that TRIM71/LIN41 is a potent regulator of miR-29a processing and its inactivation directly affects miR-29a targets. We provide an extended database of RBPs that interact with pre-miRNAs in extracts of different cell types, highlighting a widespread layer of co- and posttranscriptional regulation of miRNA biogenesis.

Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy.

  • Hu M
  • Mol. Cell
  • 2017 Apr 6

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Abstract:

Mitochondria play an integral role in cell death, autophagy, immunity, and inflammation. We previously showed that Nur77, an orphan nuclear receptor, induces apoptosis by targeting mitochondria. Here, we report that celastrol, a potent anti-inflammatory pentacyclic triterpene, binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner. Celastrol promotes Nur77 translocation from the nucleus to mitochondria, where it interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling. The interaction is mediated by an LxxLL motif in TRAF2 and results not only in the inhibition of TRAF2 ubiquitination but also in Lys63-linked Nur77 ubiquitination. Under inflammatory conditions, ubiquitinated Nur77 resides at mitochondria, rendering them sensitive to autophagy, an event involving Nur77 interaction with p62/SQSTM1. Together, our results identify Nur77 as a critical intracellular target for celastrol and unravel a mechanism of Nur77-dependent clearance of inflamed mitochondria to alleviate inflammation.

Funding information:
  • NIDA NIH HHS - 1P30 DA035756-01(United States)

A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia.

  • Cayo MA
  • Cell Stem Cell
  • 2017 Apr 6

Literature context:


Abstract:

Efforts to identify pharmaceuticals to treat heritable metabolic liver diseases have been hampered by the lack of models. However, cells with hepatocyte characteristics can be produced from induced pluripotent stem cells (iPSCs). Here, we have used hepatocyte-like cells generated from homozygous familial hypercholesterolemia (hoFH) iPSCs to identify drugs that can potentially be repurposed to lower serum LDL-C. We found that cardiac glycosides reduce the production of apolipoprotein B (apoB) from human hepatocytes in culture and the serum of avatar mice harboring humanized livers. The drugs act by increasing the turnover of apoB protein. Analyses of patient medical records revealed that the treatment of patients with cardiac glycosides reduced serum LDL-C levels. These studies highlight the effectiveness of using iPSCs to screen for potential treatments for inborn errors of hepatic metabolism and suggest that cardiac glycosides could provide an approach for reducing hepatocyte production of apoB and treating hypercholesterolemia.

Funding information:
  • NCATS NIH HHS - UL1 TR000055()
  • NHGRI NIH HHS - U01 HG006398()
  • NICHD NIH HHS - R21 HD082570()
  • NIDDK NIH HHS - F30 DK091994()
  • NIDDK NIH HHS - R01 DK055743()
  • NIDDK NIH HHS - R01 DK102716()
  • NIDDK NIH HHS - RC1 DK087377()

A Metabolic Function for Phospholipid and Histone Methylation.

  • Ye C
  • Mol. Cell
  • 2017 Apr 20

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Abstract:

S-adenosylmethionine (SAM) is the methyl donor for biological methylation modifications that regulate protein and nucleic acid functions. Here, we show that methylation of a phospholipid, phosphatidylethanolamine (PE), is a major consumer of SAM. The induction of phospholipid biosynthetic genes is accompanied by induction of the enzyme that hydrolyzes S-adenosylhomocysteine (SAH), a product and inhibitor of methyltransferases. Beyond its function for the synthesis of phosphatidylcholine (PC), the methylation of PE facilitates the turnover of SAM for the synthesis of cysteine and glutathione through transsulfuration. Strikingly, cells that lack PE methylation accumulate SAM, which leads to hypermethylation of histones and the major phosphatase PP2A, dependency on cysteine, and sensitivity to oxidative stress. Without PE methylation, particular sites on histones then become methyl sinks to enable the conversion of SAM to SAH. These findings reveal an unforeseen metabolic function for phospholipid and histone methylation intrinsic to the life of a cell.

Funding information:
  • NCI NIH HHS - P30 CA142543()
  • NIGMS NIH HHS - R01 GM094314()

Structural basis for potency differences between GDF8 and GDF11.

  • Walker RG
  • BMC Biol.
  • 2017 Mar 3

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Abstract:

BACKGROUND: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. RESULTS: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. CONCLUSIONS: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.

Funding information:
  • NCI NIH HHS - R01 CA172886()
  • NIA NIH HHS - R01 AG040019()
  • NIA NIH HHS - R01 AG047131()
  • NIA NIH HHS - R01 AG048917()
  • NIA NIH HHS - R03 AG049657()
  • NIA NIH HHS - R56 AG048917()
  • NIA NIH HHS - R56 AG052979()
  • NIDDK NIH HHS - T32 DK007260()
  • NIGMS NIH HHS - R01 GM058670()
  • NIGMS NIH HHS - R01 GM114640()

Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17.

  • Cheng X
  • Mol. Cell
  • 2017 Mar 16

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Abstract:

Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity. Next, Pacer recruits PI3KC3 and HOPS complexes to the autophagosome for their site-specific activation by anchoring to the autophagosomal SNARE Stx17. Furthermore, Pacer is crucial for the degradation of hepatic lipid droplets, the suppression of Salmonella infection, and the clearance of protein aggregates. These results not only identify Pacer as a crucial multifunctional enhancer in autophagy but also uncover both the involvement of PI3KC3 and the mediators of HOPS's specific tethering activity in autophagosome maturation.

Funding information:
  • NIDDK NIH HHS - R24 DK090962(United States)

Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.

  • Finan B
  • Cell
  • 2016 Oct 20

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Abstract:

Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

Inactivation of oncogenic cAMP-specific phosphodiesterase 4D by miR-139-5p in response to p53 activation.

  • Cao B
  • Elife
  • 2016 Jul 7

Literature context:


Abstract:

Increasing evidence highlights the important roles of microRNAs in mediating p53's tumor suppression functions. Here, we report miR-139-5p as another new p53 microRNA target. p53 induced the transcription of miR-139-5p, which in turn suppressed the protein levels of phosphodiesterase 4D (PDE4D), an oncogenic protein involved in multiple tumor promoting processes. Knockdown of p53 reversed these effects. Also, overexpression of miR-139-5p decreased PDE4D levels and increased cellular cAMP levels, leading to BIM-mediated cell growth arrest. Furthermore, our analysis of human colorectal tumor specimens revealed significant inverse correlation between the expression of miR-139-5p and that of PDE4D. Finally, overexpression of miR-139-5p suppressed the growth of xenograft tumors, accompanied by decrease in PDE4D and increase in BIM. These results demonstrate that p53 inactivates oncogenic PDE4D by inducing the expression of miR-139-5p.

Upregulation of microRNA-372 associates with tumor progression and prognosis in hepatocellular carcinoma.

  • Gu H
  • Mol. Cell. Biochem.
  • 2013 Mar 24

Literature context:


Abstract:

MicroRNA-372 (miR-372) has been demonstrated to play a crucial role in cellular proliferation and apoptosis of cancer cells. However, its effects in hepatocellular carcinoma (HCC) have not been explored. The aim of this study was to investigate the clinical significance of miR-372 in human HCC. Quantitative RT-PCR was performed to detect miR-372 expression in HCC clinical samples and cell lines. Then, Kaplan-Meier and Cox proportional regression analyses were performed to determine the association of miR-372 expression with survival of HCC patients. Moreover, the effects of miR-372 on tumorigenicity of HCC cell lines were evaluated by in vitro assays. miR-372 expression in HCC tissues was significantly higher than in the corresponding normal adjacent liver tissues (P < 0.001). There was a correlation between miR-372 upregulation and advanced TNM stage of HCC patients (P = 0.02). In addition, HCC patients with higher miR-372 expression had significantly poorer recurrence-free survival (P = 0.006) and overall survival (P = 0.001). Multivariate analysis revealed that high miR-372 expression was an independent predictor of poor prognosis (for recurrence-free survival: Hazard Ratio [HR] 6.826, P = 0.01; for overall survival: HR 9.533, P = 0.008). Moreover, in vitro assays demonstrated that the ectopic expression of miR-372 may significantly promote the cellular proliferation, invasion, and migration of HCC cell lines. Our findings showed that miR-372 may serve as a potent prognostic marker for tumor recurrence and survival of HCC patients. Furthermore, miR-372 has been identified as a promoter for tumorigenicity of HCC cells, suggesting that it might be a prospective therapeutic target for HCC.