Evidence map›Paper›PMID 24931163›Full record

ArticleOncogene2015

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

K M Dodd, J Yang, M H Shen, J R Sampson, A R Tee

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 248 papers.

0numbers the graph read from it
0cells of the map it votes in
248citing papers in PubMed
11.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

248 citing papers in PubMed, 375 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Review
  5. Review
  6. Article
  7. Insulin-like growth factor receptor signaling in physiology and disease.Signal transduction and targeted therapy · 2026
    Review
  8. Article
  9. Aging and cancer: current understandings and future perspectives.Signal transduction and targeted therapy · 2026
    Review
  10. Article
  11. Review
  12. Article
  13. Article
  14. Review
  15. Article
  16. Review
  17. Review
  18. Review
  19. Review
  20. Article

188 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

5 authors at 1 institution in 1 country.

K M DoddInstitute of Cancer and Genetics, Cardiff University, Cardiff, UK.
J YangInstitute of Cancer and Genetics, Cardiff University, Cardiff, UK.
M H ShenInstitute of Cancer and Genetics, Cardiff University, Cardiff, UK.
J R SampsonInstitute of Cancer and Genetics, Cardiff University, Cardiff, UK.
A R TeeInstitute of Cancer and Genetics, Cardiff University, Cardiff, UK.
Cardiff University · GB

Funding

Cancer Research UK 06-914/915Worldwide Cancer Research 06-0914
6 · The paper itself

Abstract

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.

Indexed as

Signal TransductionAdaptor Proteins, Signal TransducingAnimalsCarrier ProteinsCell Cycle ProteinsCell HypoxiaCystadenocarcinomaEukaryotic Initiation FactorsGene Expression Regulation, NeoplasticHEK293 CellsHumansHypoxia-Inducible Factor 1, alpha SubunitKidney NeoplasmsMechanistic Target of Rapamycin Complex 1MiceMice, KnockoutAdaptor Proteins, Signal TransducingCarrier ProteinsCell Cycle ProteinsEif4ebp1 protein, mouseEukaryotic Initiation FactorsHif1a protein, mouseHypoxia-Inducible Factor 1, alpha SubunitMechanistic Target of Rapamycin Complex 1Multiprotein ComplexesNeoplasm ProteinsPhosphoproteinsRibosomal Protein S6 Kinases, 90-kDaRps6ka1 protein, mouseStat3 protein, mouseSTAT3 Transcription FactorTOR Serine-Threonine KinasesVascular Endothelial Growth Factor Avascular endothelial growth factor A, mouse

Identifiers

PMID24931163
PMCPMC4172452
OpenAlexW2001775267

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.