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.