PMID- 19435890 OWN - NLM STAT- MEDLINE DCOM- 20090708 LR - 20220330 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 69 IP - 10 DP - 2009 May 15 TI - RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB-mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN. PG - 4107-11 LID - 10.1158/0008-5472.CAN-09-0474 [doi] AB - Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a negative feedback loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-kappaB (NF-kappaB) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR negative feedback loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-kappaB-dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-kappaB activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel negative regulation of mTOR signaling at the transcriptional level by the NF-kappaB pathway. Our data suggest that the RIP1-NF-kappaB status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis. FAU - Park, Seongmi AU - Park S AD - Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8813, USA. FAU - Zhao, Dawen AU - Zhao D FAU - Hatanpaa, Kimmo J AU - Hatanpaa KJ FAU - Mickey, Bruce E AU - Mickey BE FAU - Saha, Debabrata AU - Saha D FAU - Boothman, David A AU - Boothman DA FAU - Story, Michael D AU - Story MD FAU - Wong, Eric T AU - Wong ET FAU - Burma, Sandeep AU - Burma S FAU - Georgescu, Maria-Magdalena AU - Georgescu MM FAU - Rangnekar, Vivek M AU - Rangnekar VM FAU - Chauncey, Sandili S AU - Chauncey SS FAU - Habib, Amyn A AU - Habib AA LA - eng GR - R01 CA102792/CA/NCI NIH HHS/United States GR - P30 CA142543/CA/NCI NIH HHS/United States GR - UL1 RR024982/RR/NCRR NIH HHS/United States GR - UL1 RR024982-017793/RR/NCRR NIH HHS/United States GR - R01 CA139217/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20090512 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (AGFG1 protein, human) RN - 0 (NF-kappa B) RN - 0 (Nuclear Pore Complex Proteins) RN - 0 (RNA-Binding Proteins) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) 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 - EC 3.1.3.67 (PTEN protein, human) SB - IM MH - Brain Neoplasms/*genetics MH - Gene Expression Regulation, Neoplastic MH - Glioblastoma/*genetics MH - Humans MH - NF-kappa B/genetics/metabolism MH - Nuclear Pore Complex Proteins/*genetics/*metabolism MH - PTEN Phosphohydrolase/*genetics/metabolism MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Polymerase Chain Reaction MH - Promoter Regions, Genetic MH - Protein Kinases MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RNA-Binding Proteins/*genetics/*metabolism MH - TOR Serine-Threonine Kinases PMC - PMC2683913 MID - NIHMS106850 EDAT- 2009/05/14 09:00 MHDA- 2009/07/09 09:00 PMCR- 2010/05/15 CRDT- 2009/05/14 09:00 PHST- 2009/05/14 09:00 [entrez] PHST- 2009/05/14 09:00 [pubmed] PHST- 2009/07/09 09:00 [medline] PHST- 2010/05/15 00:00 [pmc-release] AID - 0008-5472.CAN-09-0474 [pii] AID - 10.1158/0008-5472.CAN-09-0474 [doi] PST - ppublish SO - Cancer Res. 2009 May 15;69(10):4107-11. doi: 10.1158/0008-5472.CAN-09-0474. Epub 2009 May 12.