Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex

Brugarolas, James; Lei, Kui; Hurley, Rebecca L.; Manning, Brendan D.; Reiling, Jan H.; Hafen, Ernst; Witters, Lee A.; Ellisen, Leif W.; Kaelin, William G.

doi:10.1101/gad.1256804

Cited by 1,199 publications

(1,135 citation statements)

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“…It is well established that HIF1a promotes carcinogenesis by various mechanisms, including the enhancement of tumor angiogenesis, invasion, metastasis and resistance to therapy (Semenza, 2003;Bertout et al, 2008). Our observation that HIF1a inhibits ALK þ TCL cell proliferation by partially inhibiting mTORC1 activation is in agreement with the previous finding that HIF1a inhibits TOR in Drosophila by activating the REDD analog protein (Brugarolas et al, 2004). This induced, mTORC1-dependent relative cell quiescence combined with the simultaneous fostering by HIF1a of the VEGF synthesis (Figure 4d) indicates that under suboptimal, hypoxic conditions, HIF1a adjusts the growth rate of ALK þ TCL cells and promotes blood vessel formation to increase oxygen supply and, ultimately, optimizes conditions for an undisturbed tumor expansion.…”

Section: Npm/alk-stat3 Pathway Induces Hif1a Expression M Marzec Et Alsupporting

confidence: 93%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

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Section: Npm/alk-stat3 Pathway Induces Hif1a Expression M Marzec Et Alsupporting

confidence: 93%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

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“…Many of these target genes have been found to form feedback loops via the regulation of the hypoxia-related activity of the mTOR pathway. These include REDD1 that has been reported to activate the Tuberous Sclerosis Complex 1/2 (TSC1/2) [75]. The TSC1/2 possesses GTPase activating function that renders the mTOR activator RHEB inactive [76].…”

Section: Crosstalk Between the Hif And Other Regulatory Pathwaysmentioning

confidence: 99%

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

2016

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“…The control of mTORC2 activity is not well understood, but one study suggested that Rheb-GTP, the activator of mTORC1, inhibits mTORC2 (REF. 34). If this is the case, then how are both mTORC1 and mTORC2 activated during infection with viruses such as HCMV?…”

Section: The Poxviridaementioning

confidence: 99%

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

et al. 2008

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The successful replication of mammalian DNA viruses requires that they gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Mammalian DNA viruses have evolved various mechanisms to activate this pathway to obtain the benefits of Akt activation, including the maintenance of translation through the activation of mTOR. In addition, viruses must overcome the inhibition of this pathway that results from the activation of cellular stress responses during viral infection. This Review will discuss the range of mechanisms that mammalian DNA viruses use to activate this pathway, as well as the multiple mechanisms these viruses have evolved to circumvent inhibitory stress signalling.The successful replication of mammalian DNA viruses, such as polyomaviruses (also called papovaviruses), adenoviruses, herpesviruses and poxviruses, requires viral adaptation of the host cell to establish an environment that can accommodate the increased demands for nutrients, energy and macromolecular synthesis that accompany viral infection. All DNA viruses must gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival. The phosphatidylinositol 3′-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is one such pathway. Virtually all mammalian viruses, both DNA and RNA, must regulate this pathway, either by activating or inactivating some aspect of it 1 . In general, mammalian DNA viruses activate this pathway at some point in their life cycle to benefit from the growth, metabolic, anti-apoptotic and translational functions that the pathway controls. However, a viral mechanism for activating this pathway is not enough; to maintain control, viruses must also overcome the many controls that are used to inhibit this pathway when cellular stress responses are activated during viral infection.Correspondence to J.C.A., e-mail: alwine@mail.med.upenn.edu. * These authors contributed equally to this work. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe substantial alterations in cellular physiology that are induced by a viral lytic infectionas a result of nutrient depletion, energy depletion, hypoxia and endoplasmic reticulum stress -activate cellular stress responses that alert the cell to problems with metabolic and synthetic processes. The resulting stress signalling activates mechanisms that either alleviate the problems or, if this is not possible, induce apoptosis. Stress signalling has many effects that can be either beneficial or detrimental to viral growth. One example of a detrimental effect is inhibition of translation, which is among the most common consequences of cellular stress responses 2-6 . Although the inhibition of this energy-intensive process permits the cell to recover from stress,...

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Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex

Abstract: Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is[Keywords: Tuberous Sclerosis Complex; TSC1; TSC2; REDD1/RTP801; mTOR; Hypoxia] Supplemental material is available at http://www.genesdev.org.

Cited by 1,199 publications

References 53 publications

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

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