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10.1038/onc.2014.164 http://scihub22266oqcxt.onion/10.1038/onc.2014.164 C4172452!4172452 !24931163     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24931163 &cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\24931163 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Oncogene 2015 ; 34 (17 ): 2239-50 Nephropedia Template TP {{tp|p=24931163 |t=2015. mTORC1 drives HIF-1? and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3 |pdf=|usr=}}{{24931163 }} gab.com Text mTORC1 drives HIF-1 and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3 JO: Oncogene http://www.kidney.de/pget.php?&tw=1&pmid=24931163 #FOAvip Recent clinical trials using rapalogues in tuberous sclerosis complex show regression in volume of typically vascularised tumours including angiomyolipomas and subependymal giant cell astrocytomas. By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur, in part, through suppression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1? protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/- mouse model. We established that mTORC1 drives HIF-1? protein accumulation through enhanced transcription of HIF-1? mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1? mRNA transcription. mTORC1 also regulates HIF-1? synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1? degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1? synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1? protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1? translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1? but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1?-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1?, VEGF-A and angiogenesis via multiple signalling mechanisms. Twit Text FOAVip mTORC1 drives HIF-1 and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3 ????Oncogene http://www.kidney.de/pget.php?&tw=1&pmid=24931163 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24931163 #FOAvip English Wikipedia <ref>{{Cite pmid|24931163 }}</ref> mTORC1 drives HIF-1? and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3 #MMPMID24931163 Dodd KM ; Yang J ; Shen MH ; Sampson JR ; Tee AR Oncogene 2015[Apr]; 34 (17 ): 2239-50 PMID24931163 show ga Recent clinical trials using rapalogues in tuberous sclerosis complex show regression in volume of typically vascularised tumours including angiomyolipomas and subependymal giant cell astrocytomas. By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur, in part, through suppression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1? protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/- mouse model. We established that mTORC1 drives HIF-1? protein accumulation through enhanced transcription of HIF-1? mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1? mRNA transcription. mTORC1 also regulates HIF-1? synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1? degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1? synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1? protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1? translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1? but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1?-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1?, VEGF-A and angiogenesis via multiple signalling mechanisms. |*Signal Transduction [MESH] |Adaptor Proteins, Signal Transducing [MESH] |Animals [MESH] |Carrier Proteins/genetics/*metabolism [MESH] |Cell Cycle Proteins [MESH] |Cell Hypoxia/genetics [MESH] |Cystadenocarcinoma/genetics/*metabolism/pathology [MESH] |Eukaryotic Initiation Factors [MESH] |Gene Expression Regulation, Neoplastic [MESH] |HEK293 Cells [MESH] |Humans [MESH] |Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism [MESH] |Kidney Neoplasms/genetics/*metabolism/pathology [MESH] |Mechanistic Target of Rapamycin Complex 1 [MESH] |Mice [MESH] |Mice, Knockout [MESH] |Multiprotein Complexes/genetics/*metabolism [MESH] |Neoplasm Proteins/genetics/*metabolism [MESH] |Phosphoproteins/genetics/*metabolism [MESH] |Ribosomal Protein S6 Kinases, 90-kDa/genetics/*metabolism [MESH] |STAT3 Transcription Factor/genetics/*metabolism [MESH] |TOR Serine-Threonine Kinases/genetics/*metabolism [MESH]mTORC1 drives HIF-1? and VEGF-A signalling via multiple mechanisms inv(epmc).pdf DeepDyve Pubget Overpricing