PMID- 19808964 OWN - NLM STAT- MEDLINE DCOM- 20091124 LR - 20211203 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 69 IP - 20 DP - 2009 Oct 15 TI - A novel PTEN-dependent link to ubiquitination controls FLIPS stability and TRAIL sensitivity in glioblastoma multiforme. PG - 7911-6 LID - 10.1158/0008-5472.CAN-09-1287 [doi] AB - 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. FAU - Panner, Amith AU - Panner A AD - Brain Tumor Research Center, Department of Neurological Surgery and University of California San Francisco Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158-9001, USA. FAU - Crane, Courtney A AU - Crane CA FAU - Weng, Changjiang AU - Weng C FAU - Feletti, Alberto AU - Feletti A FAU - Parsa, Andrew T AU - Parsa AT FAU - Pieper, Russell O AU - Pieper RO LA - eng GR - R01 CA115638/CA/NCI NIH HHS/United States GR - R01 CA136774-04/CA/NCI NIH HHS/United States GR - R01 CA115638-05/CA/NCI NIH HHS/United States GR - CA136774/CA/NCI NIH HHS/United States GR - P50 CA097257/CA/NCI NIH HHS/United States GR - CA097257/CA/NCI NIH HHS/United States GR - R01 CA136774/CA/NCI NIH HHS/United States GR - CA115638/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20091006 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein) RN - 0 (RNA, Small Interfering) RN - 0 (Repressor Proteins) RN - 0 (TNF-Related Apoptosis-Inducing Ligand) RN - 0 (Ubiquitin) RN - EC 2.3.2.26 (ITCH protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Apoptosis MH - Blotting, Western MH - CASP8 and FADD-Like Apoptosis Regulating Protein/*chemistry/*metabolism MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm MH - Glioblastoma/*metabolism/pathology MH - Half-Life MH - Humans MH - Immunoprecipitation MH - Mice MH - Mice, Knockout MH - PTEN Phosphohydrolase/*physiology MH - Protein Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RNA, Small Interfering/pharmacology MH - Repressor Proteins/antagonists & inhibitors/genetics/*metabolism MH - Signal Transduction MH - Sirolimus/pharmacology MH - TNF-Related Apoptosis-Inducing Ligand/*metabolism MH - TOR Serine-Threonine Kinases MH - Ubiquitin/metabolism MH - Ubiquitin-Protein Ligases/antagonists & inhibitors/genetics/*metabolism MH - Ubiquitination MH - Xenograft Model Antitumor Assays PMC - PMC3229302 MID - NIHMS317667 COIS- Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. EDAT- 2009/10/08 06:00 MHDA- 2009/12/16 06:00 PMCR- 2011/12/02 CRDT- 2009/10/08 06:00 PHST- 2009/10/08 06:00 [entrez] PHST- 2009/10/08 06:00 [pubmed] PHST- 2009/12/16 06:00 [medline] PHST- 2011/12/02 00:00 [pmc-release] AID - 0008-5472.CAN-09-1287 [pii] AID - 10.1158/0008-5472.CAN-09-1287 [doi] PST - ppublish SO - Cancer Res. 2009 Oct 15;69(20):7911-6. doi: 10.1158/0008-5472.CAN-09-1287. Epub 2009 Oct 6.