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Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase.

Cancer cell | 2018

KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.

Pubmed ID: 29316436 RIS Download

Mesh terms: Activating Transcription Factor 4 | Animals | Asparaginase | Aspartate-Ammonia Ligase | Carcinoma, Non-Small-Cell Lung | Cell Line, Tumor | Homeostasis | Humans | Lung Neoplasms | Mice | Proto-Oncogene Proteins p21(ras)

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The Cancer Genome Atlas (tool)

RRID:SCR_003193

Project exploring the spectrum of genomic changes involved in more than 20 types of human cancer that provides a platform for researchers to search, download, and analyze data sets generated. As a pilot project it confirmed that an atlas of changes could be created for specific cancer types. It also showed that a national network of research and technology teams working on distinct but related projects could pool the results of their efforts, create an economy of scale and develop an infrastructure for making the data publicly accessible. Its success committed resources to collect and characterize more than 20 additional tumor types. Components of the TCGA Research Network: * Biospecimen Core Resource (BCR); Tissue samples are carefully cataloged, processed, checked for quality and stored, complete with important medical information about the patient. * Genome Characterization Centers (GCCs); Several technologies will be used to analyze genomic changes involved in cancer. The genomic changes that are identified will be further studied by the Genome Sequencing Centers. * Genome Sequencing Centers (GSCs); High-throughput Genome Sequencing Centers will identify the changes in DNA sequences that are associated with specific types of cancer. * Proteome Characterization Centers (PCCs); The centers, a component of NCI's Clinical Proteomic Tumor Analysis Consortium, will ascertain and analyze the total proteomic content of a subset of TCGA samples. * Data Coordinating Center (DCC); The information that is generated by TCGA will be centrally managed at the DCC and entered into the TCGA Data Portal and Cancer Genomics Hub as it becomes available. Centralization of data facilitates data transfer between the network and the research community, and makes data analysis more efficient. The DCC manages the TCGA Data Portal. * Cancer Genomics Hub (CGHub); Lower level sequence data will be deposited into a secure repository. This database stores cancer genome sequences and alignments. * Genome Data Analysis Centers (GDACs) - Immense amounts of data from array and second-generation sequencing technologies must be integrated across thousands of samples. These centers will provide novel informatics tools to the entire research community to facilitate broader use of TCGA data. TCGA is actively developing a network of collaborators who are able to provide samples that are collected retrospectively (tissues that had already been collected and stored) or prospectively (tissues that will be collected in the future).

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cBioPortal (tool)

RRID:SCR_014555

A portal that provides visualization, analysis and download of large-scale cancer genomics data sets.

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ATF4-human antibody (antibody)

RRID:AB_2616025

This unknown targets ATF4

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Cleaved PARP (Asp214) (D64E10) XP Rabbit mAb antibody (antibody)

RRID:AB_10699459

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eIF2alpha (D7D3) XP Rabbit mAb antibody (antibody)

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Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb antibody (antibody)

RRID:AB_916156

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Asparagine synthetase (G-10) antibody (antibody)

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Monoclonal Anti-beta-Actin antibody produced in mouse (antibody)

RRID:AB_476697

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GCN2 Antibody (antibody)

RRID:AB_2277617

This unknown targets GCN2

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Phospho-Akt (Ser473) antibody (antibody)

RRID:AB_2315049

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xCT/SLC7A11 (D2M7A) Rabbit Antibody (antibody)

RRID:AB_2687474

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4F2hc/CD98 (D6O3P) Rabbit Antibody (antibody)

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ASCT2 (D7C12) Rabbit mAb antibody (antibody)

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Akt Antibody (antibody)

RRID:AB_329827

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p44/42 MAPK (Erk1/2) (137F5) Rabbit mAb antibody (antibody)

RRID:AB_390779

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Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) antibody (antibody)

RRID:AB_2315112

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