The Akt of translational control

Ruggero, Davide; Sonenberg, Nahum

doi:10.1038/sj.onc.1209098

Cited by 186 publications

(167 citation statements)

References 127 publications

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“…It also stimulates the activity of translation initiation factors and ribosome biosynthesis. 36 Recently, Abdul-Ghani et al 37 reported that inhibition of PI3K results in an increase of intracellular doxorubicin concentration in a competitive manner. Furthermore, flunarizine might induce a loss of PTEN function, which used to trigger the activation of the PI3K/Akt pathway.…”

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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“…Relevant to studies of the pro-apoptotic protein kinase DAPK, cell apoptotic or survival signals affect protein synthesis through phosphorylation of translation initiation factors and ribosomal components (44). One of these components is ribosomal protein S6.…”

Section: Discussionmentioning

confidence: 99%

Death-Associated Protein Kinase Phosphorylates Mammalian Ribosomal Protein S6 and Reduces Protein Synthesis

et al. 2006

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Death associated protein kinase (DAPK) is a pro-apoptotic, calcium/calmodulin regulated protein kinase that is a drug discovery target for neurodegenerative disorders. Despite the potential profound physiological role of DAPK in neuronal function and pathophysiology, the endogenous substrate(s) of this kinase and the mechanisms via which DAPK elicits its biological action remain largely unknown. We report here that the mammalian 40S ribosomal protein S6 is a DAPK substrate. Results from immunoprecipitation experiments are consistent with endogenous DAPK being associated with endogenous S6 in rat brain. When S6 is a component of the 40S ribosomal subunit complex, DAPK selectively phosphorylates it at serine 235, one of the five sites in S6 that are phosphorylated by the S6 kinase family of proteins. The amino acid sequence flanking serine 235 matches the established pattern for DAPK peptide and protein substrates. Kinetic analyses using purified 40S subunits revealed a K m value of 9 μM, consistent with S6 being a potential physiological substrate of DAPK. This enzyme-substrate relationship has functional significance. DAPK suppresses translation in rabbit reticulocyte lysate and treatment of neuroblastoma cells with a stimulator of DAPK reduces protein synthesis. In both cases, suppression of translation correlates with increased phosphorylation of S6 at serine 235. These results demonstrate that DAPK is an S6 kinase and provide evidence for a novel role of DAPK in regulation of translation. KeywordsApoptosis; synaptic plasticity; translational control; protein synthesis; DAPK; ribosomal protein S6; S6 kinase Death associated protein kinase (DAPK) is a calcium and calmodulin (CaM)-regulated serine/threonine protein kinase implicated in the pathophysiology characteristic of diverse † A.M.S. and A

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“…Although Akt has been demonstrated to phosphorylate mTOR directly, the role of these phosphorylation sites remains unclear. Phosphorylation of mTOR by Akt at serine 2448 might not correlate with mTOR activation, therefore, pmTOR 2448 may not necessary be involved with the development of HRPC, and a more appropriate marker of mTOR activation could be S6Kinase (Ruggero and Sonenberg, 2005).…”

Section: Protein Expression Patternsmentioning

confidence: 99%

Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients

et al. 2008

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Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (P ¼ 0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (P ¼ 0.014), and an increase in expression of pAkt 473 and pAR 210 were associated with decreased disease-specific survival (P ¼ 0.0019 and 0.0015, respectively). Protein expression of pAkt 473 and pAR 210 also strongly correlated (Po0.001, c.c. ¼ 0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target.

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The Akt of translational control

Cited by 186 publications

References 127 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

Death-Associated Protein Kinase Phosphorylates Mammalian Ribosomal Protein S6 and Reduces Protein Synthesis

Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients

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