HIF2α activates mTORC1 via SLC7A5 to promote proliferation in tumors lacking VHL.
Major finding: HIF2α activates mTORC1 via SLC7A5 to promote proliferation in tumors lacking VHL.
Mechanism: HIF2α induces Slc7a5 transcription to sustain mTORC1 activity when amino acids are limited.
Impact: In contrast to HIF1α and other oxygen-sensing pathways, HIF2α promotes mTORC1 activation.
Hypoxia-inducible factor 1α (HIF1α) activation and some HIF-independent pathways suppress proliferation and protein translation under hypoxic stress by inhibiting mTOR complex 1 (mTORC1), which regulates cell growth in response to oxygen deprivation. In contrast, HIF2α stimulates proliferation in tissues such as the liver and enhances the growth of von Hippel-Lindau (VHL)–deficient renal cell carcinoma (RCC). To investigate the mechanisms underlying the tumor-promoting properties of HIF2α, Elorza and colleagues tested whether HIF2α differentially regulates mTORC1 activity. Under conditions of reduced amino acid availability similar to those in the intratumoral microenvironment, expression of HIF2α but not HIF1α resulted in phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and ribosomal protein S6 (rpS6), indicative of increased mTORC1 activity. This effect was dependent on HIF2α-mediated transcriptional induction of solute carrier family 7 (amino acid transporter light chain, L system) , member 5 (Slc7a5), which encodes for an amino acid carrier necessary for mTORC1 activity. SLC7A5-triggered mTORC1 activation augmented cell proliferation in low amino acid conditions and promoted the growth of VHL-deficient xenograft tumors; increased SLC7A5 expression was also detected in human RCC samples, supporting a critical role for this pathway in HIF2α-driven tumor cell proliferation. In addition, HIF2α expression was specifically required for mTORC1 activation induced by hypoxia or Vhl ablation in the lung, which expresses high levels of Hif2a, and in Vhl-deficient liver tissue, as loss of Hif2a impaired Slc7a5 upregulation and downstream phosphorylation of 4EBP1 and rpS6. These results identify hypoxia and HIF2α as important activators of mTORC1 under certain physiologic conditions and provide insight into the molecular mechanism by which HIF2α promotes tumorigenesis.
Elorza A, Soro-Arnáiz I, Meléndez-Rodríguez F, Rodríguez-Vaello V, Marsboom G, de Cárcer G, et al. HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell 2012 Oct 24 [Epub ahead of print].
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