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A novel PTEN-dependent link to ubiquitination controls FLIPS stability and TRAIL sensitivity in glioblastoma multiforme.

Phosphatase and tensin homologue (PTEN) loss and activation of the Akt-mammalian target of rapamycin (mTOR) pathway increases mRNA translation, increases levels of the antiapoptotic protein FLIP(S), and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioblastoma multiforme (GBM). In PTEN-deficient GBM cells, however, the FLIP(S) protein also exhibited a longer half-life than in PTEN mutant GBM cells, and this longer half-life correlated with decreased FLIP(S) polyubiquitination. FLIP(S) half-life in PTEN mutant GBM cells was reduced by exposure to an Akt inhibitor, but not to rapamycin, suggesting the existence of a previously undescribed, mTOR-independent linkage between PTEN and the ubiquitin-dependent control of protein stability. Total levels of the candidate FLIP(S) E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4) were comparable in PTEN wild-type (WT) and PTEN mutant GBM cells, although in PTEN-deficient cells, AIP4 was maintained in a stable polyubiquitinated state that was less able to associate with FLIP(S) or with the FLIP(S)-containing death inducing signal complex. Small interfering RNA-mediated suppression of AIP4 levels in PTEN WT cells decreased FLIP(S) ubiquitination, prolonged FLIP(S) half-life, and increased TRAIL resistance. Similarly, the Akt activation that was previously shown to increase TRAIL resistance did not alter AIP4 levels, but increased AIP4 ubiquitination, increased FLIP(S) steady-state levels, and suppressed FLIP(S) ubiquitination. These results define the PTEN-Akt-AIP4 pathway as a key regulator of FLIP(S) ubiquitination, FLIP(S) stability, and TRAIL sensitivity and also define a novel link between PTEN and the ubiquitin-mediated control of protein stability.

Pubmed ID: 19808964

Authors

  • Panner A
  • Crane CA
  • Weng C
  • Feletti A
  • Parsa AT
  • Pieper RO

Journal

Cancer research

Publication Data

October 15, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA097257
  • Agency: NCI NIH HHS, Id: CA115638
  • Agency: NCI NIH HHS, Id: CA136774
  • Agency: NCI NIH HHS, Id: R01 CA115638
  • Agency: NCI NIH HHS, Id: R01 CA115638-05
  • Agency: NCI NIH HHS, Id: R01 CA136774
  • Agency: NCI NIH HHS, Id: R01 CA136774-04

Mesh Terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Glioblastoma
  • Half-Life
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase
  • Protein Kinases
  • Proto-Oncogene Proteins c-akt
  • RNA, Small Interfering
  • Repressor Proteins
  • Signal Transduction
  • Sirolimus
  • TNF-Related Apoptosis-Inducing Ligand
  • TOR Serine-Threonine Kinases
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Xenograft Model Antitumor Assays