دورية أكاديمية
أعرض في EDS

mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3.

التفاصيل البيبلوغرافية
العنوان: mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3.
المؤلفون: Dodd KM; Institute of Cancer and Genetics, Cardiff University, Cardiff, UK., Yang J; Institute of Cancer and Genetics, Cardiff University, Cardiff, UK., Shen MH; Institute of Cancer and Genetics, Cardiff University, Cardiff, UK., Sampson JR; Institute of Cancer and Genetics, Cardiff University, Cardiff, UK., Tee AR; Institute of Cancer and Genetics, Cardiff University, Cardiff, UK.
المصدر: Oncogene [Oncogene] 2015 Apr 23; Vol. 34 (17), pp. 2239-50. Date of Electronic Publication: 2014 Jun 16.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
مواضيع طبية MeSH: Signal Transduction*, Carrier Proteins/*metabolism , Cystadenocarcinoma/*metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism , Kidney Neoplasms/*metabolism , Multiprotein Complexes/*metabolism , Neoplasm Proteins/*metabolism , Phosphoproteins/*metabolism , Ribosomal Protein S6 Kinases, 90-kDa/*metabolism , STAT3 Transcription Factor/*metabolism , TOR Serine-Threonine Kinases/*metabolism , Vascular Endothelial Growth Factor A/*metabolism, Adaptor Proteins, Signal Transducing ; Animals ; Carrier Proteins/genetics ; Cell Cycle Proteins ; Cell Hypoxia/genetics ; Cystadenocarcinoma/genetics ; Cystadenocarcinoma/pathology ; Eukaryotic Initiation Factors ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Kidney Neoplasms/genetics ; Kidney Neoplasms/pathology ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Knockout ; Multiprotein Complexes/genetics ; Neoplasm Proteins/genetics ; Phosphoproteins/genetics ; Ribosomal Protein S6 Kinases, 90-kDa/genetics ; STAT3 Transcription Factor/genetics ; TOR Serine-Threonine Kinases/genetics ; Vascular Endothelial Growth Factor A/genetics
مستخلص: 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-1α 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-1α protein accumulation through enhanced transcription of HIF-1α 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-1α mRNA transcription. mTORC1 also regulates HIF-1α 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-1α degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1α synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1α protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1α translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1α but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1α-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-1α, VEGF-A and angiogenesis via multiple signalling mechanisms.
التعليقات: Comment in: J Urol. 2016 Feb;195(2):524. (PMID: 26853037)
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معلومات مُعتمدة: 06-0914 United Kingdom AICR_ Worldwide Cancer Research; 06-914/915 United Kingdom CRUK_ Cancer Research UK
فهرسة مساهمة: Indexing Agency: NLM Local ID #: EMS58338.
المشرفين على المادة: 0 (Adaptor Proteins, Signal Transducing)
0 (Carrier Proteins)
0 (Cell Cycle Proteins)
0 (Eif4ebp1 protein, mouse)
0 (Eukaryotic Initiation Factors)
0 (Hif1a protein, mouse)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
0 (Multiprotein Complexes)
0 (Neoplasm Proteins)
0 (Phosphoproteins)
0 (STAT3 Transcription Factor)
0 (Stat3 protein, mouse)
0 (Vascular Endothelial Growth Factor A)
0 (vascular endothelial growth factor A, mouse)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
EC 2.7.11.1 (Rps6ka1 protein, mouse)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20140617 Date Completed: 20150629 Latest Revision: 20220129
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4172452
DOI: 10.1038/onc.2014.164
PMID: 24931163
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5594
DOI:10.1038/onc.2014.164