Akt-dependent transformation: there is more to growth than just surviving

Plas, David R.; Thompson, Craig B.

doi:10.1038/sj.onc.1209097

Cited by 391 publications

(331 citation statements)

References 99 publications

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“…Akt serves for cell survival through phosphorylation-mediated protein modification, including inactivation of tumor suppressors and activation of trophic signal cascades. 35 PI3K/Akt signaling also upregulates transport and metabolism of glucose and amino acids. It also stimulates the activity of translation initiation factors and ribosome biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

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Section: Discussionmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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“…Broadly, these can originate from either enhancing signals that directly increase glycolysis or from inhibiting energy metabolism by the mitochondria, rendering glycolysis the major source of ATP. Glycolytic enzymes are induced by oncogenes (Dang and Semenza, 1999;Plas and Thompson, 2005) or by the hypoxia-inducible transcription factor (HIF) (Maxwell, 2005a), whereas oxidative phosphorylation can be inhibited by mutations in mitochondrial DNA (Carew and Huang, 2002;Modica-Napolitano and Singh, 2004) or a dysfunctional TCA cycle owing to loss of function of mitochondrial tumour suppressor genes (Eng et al, 2003;Gottlieb and Tomlinson, 2005). This review focuses on a newly discovered biochemical link between the loss of mitochondrial tumour suppressors and the induction of glycolysis by the HIF pathway.…”

Section: Enhanced Glycolysis In Cancer Cellsmentioning

confidence: 99%

“…A pseudohypoxic response in tumours can be achieved either by accelerated mammalian target of rapamycin (mTOR)-dependent translation or by impaired degradation of HIFa (Figure 2). The mTOR-dependent translation of HIFa is induced by the loss of the Tsc1, Tsc2 or Lkb1 tumour suppressor genes and potentially by activation via the Akt pathway (Inoki et al, 2005;Plas and Thompson, 2005). Impaired HIFa degradation is severely manifest in cells deficient for the VHL tumour suppressor gene (Kim and Kaelin, 2004).…”

Section: Succinate Dehydrogenase and Fumarate Hydratasementioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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“…Akt activation can occur in response to tropic factors, such as insulin, by several mechanisms [8][9][10] (FIG. 1), the best understood of which involves PI3K.…”

Section: Pi3k-akt-mtor Signallingmentioning

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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Akt-dependent transformation: there is more to growth than just surviving

Cited by 391 publications

References 99 publications

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

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

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