Stress-mediated translational control in cancer cells

Leprivier, Gabriel; Rotblat, Barak; Khan, Debjit; Jan, Eric; Sorensen, Poul H.

doi:10.1016/j.bbagrm.2014.11.002

Cited by 110 publications

(119 citation statements)

References 196 publications

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“…Thus, the control of HB translation involves the coordination of ribosomal structural components and associated factors that are necessary for the assembly of functional polysomes. That the former group is subject to significant Myc-dependent regulation, whereas the latter group is not, may reflect the participation of many of its members in processes other than translation (33,42) Both the inability to fully maximize ribosomal biogenesis and the disparate stoichiometries of the structural and functional components of the translational machinery may contribute to the slower growth rate of KO HBs and perhaps to inefficiencies or loss of fidelity in global protein synthetic rates. Our studies on mitochondrial function, substrate flux, acetyl-CoA levels, and metabolic pathway transcriptional profiling also point to a growth-limiting role for glucose-derived acetyl-CoA in Myc KO HBs.…”

Section: Discussionmentioning

confidence: 99%

Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma

Wang

Edmunds

et al. 2016

Journal of Biological Chemistry

244

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Edited by Eric FearonHepatoblastoma (HB) is associated with aberrant activation of the ␤-catenin and Hippo/YAP signaling pathways. Overexpression of mutant ␤-catenin and YAP in mice induces HBs that express high levels of c-Myc (Myc). In light of recent observations that Myc is unnecessary for long-term hepatocyte proliferation, we have now examined its role in HB pathogenesis using the above model. Although Myc was found to be dispensable for in vivo HB initiation, it was necessary to sustain rapid tumor growth. Gene expression profiling identified key molecular differences between myc ؉/؉ (WT) and myc ؊/؊ (KO) hepatocytes and HBs that explain these behaviors. In HBs, these included both Myc-dependent and Myc-independent increases in families of transcripts encoding ribosomal proteins, non-structural factors affecting ribosome assembly and function, and enzymes catalyzing glycolysis and lipid bio-synthesis. In contrast, transcripts encoding enzymes involved in fatty acid ␤-oxidation were mostly down-regulated. Myc-independent metabolic changes associated with HBs included dramatic reductions in mitochondrial mass and oxidative function, increases in ATP content and pyruvate dehydrogenase activity, and marked inhibition of fatty acid ␤-oxidation (FAO). Myc-dependent metabolic changes included higher levels of neutral lipid and acetylCoA in WT tumors. The latter correlated with higher histone H3 acetylation. Collectively, our results indicate that the role of Myc in HB pathogenesis is to impose mutually dependent changes in gene expression and metabolic reprogramming that are unattainable in non-transformed cells and that cooperate to maximize tumor growth.

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Section: Discussionmentioning

confidence: 99%

Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma

Wang

Edmunds

et al. 2016

Journal of Biological Chemistry

244

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“…Similarly, in a genomewide functional screen, CReP down-regulation was identified to increase sensitivity to tamoxifen (64). The outcome of fine-tuning the eIF2α phosphorylation level under intratumoral stresses is likely to affect the balance between death and survival (44,65,66). It is therefore tempting to speculate that sustained pharmacological activation of ISR could modify the cell fate decision process and tilt the balance in favor of death.…”

Section: Discussionmentioning

confidence: 99%

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Gassart

Bujisic

Zaffalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

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“…Impaired stress responses contribute to human age‐related diseases such as diabetes and neurodegenerative disorders (Hetz, Chevet & Harding, 2013; Lin & Beal, 2006), and likely also contribute to aging (Hekimi, Lapointe & Wen, 2011; Shore & Ruvkun, 2013). However, these adaptive responses also protect pathogens and cancer cells against cytotoxic drugs and the immune system (Leprivier, Rotblat, Khan, Jan & Sorensen, 2015; Rankin & Giaccia, 2016). Accordingly, there is widespread interest in defining the mechanisms involved in coordinating these transcriptional responses.…”

Section: Introductionmentioning

confidence: 99%

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

et al. 2018

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SummaryEndogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator‐activated receptor α (PPARα), Caenorhabditis elegans NHR‐49 is a well‐established regulator of lipid metabolism. Here, we reveal that NHR‐49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro‐longevity gene fmo‐2/flavin‐containing monooxygenase. These NHR‐49‐dependent, stress‐responsive genes are also upregulated in long‐lived glp‐1/notch receptor mutants, with two of them making critical contributions to the oxidative stress resistance of wild‐type and long‐lived glp‐1 mutants worms. Similar to its role in lipid metabolism, NHR‐49 requires the mediator subunit mdt‐15 to promote stress‐induced gene expression. However, NHR‐49 acts independently from the transcription factor hlh‐30/TFEB that also promotes fmo‐2 expression. We show that activation of the p38 MAPK, PMK‐1, which is important for adaptation to a variety of stresses, is also important for peroxide‐induced expression of a subset of NHR‐49‐dependent genes that includes fmo‐2. However, organic peroxide increases NHR‐49 protein levels, by a posttranscriptional mechanism that does not require PMK‐1 activation. Together, these findings establish a new role for the HNF4/PPARα‐related NHR‐49 as a stress‐activated regulator of cytoprotective gene expression.

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Stress-mediated translational control in cancer cells

Cited by 110 publications

References 196 publications

Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma

Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

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