Regulation of Translational Initiation during Cellular Responses to Stress

Brostrom, Charles O.; Brostrom, Margaret A.

doi:10.1016/s0079-6603(08)60034-3

Cited by 265 publications

(213 citation statements)

References 177 publications

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“…In order to gain further insight into the role of PKR in regulating TCTP levels under proapoptotic conditions, we studied the regulation of TCTP levels in PKR-knockout cells under various stress conditions and observed PKR-dependent downregulation of the protein under Ca þ þ -stress conditions. An involvement of PKR in cellular reactions to Ca þ þ stress was suspected earlier (Brostrom and Brostrom, 1998), and it was recently demonstrated that ER stresses activate PKR (Lee et al, 2007). .…”

Section: Discussionmentioning

confidence: 93%

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

et al. 2009

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Section: Discussionmentioning

confidence: 93%

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

et al. 2009

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“…Phosphorylation of its a-subunit (eIF2a) leads to the inhibition of translation initiation as the phosphorylated form acts as a competitive inhibitor of eIF2B. 22 In many cell types relatively low levels of eIF2a phosphorylation can exert a marked inhibition on translation as cellular levels of eIF2 exceed those of eIF2B. 23 The level of phosphorylation of eIF2a was assessed by Western blot analysis with an antibody that recognises eIF2a when phosphorylated at Ser51 (P-eIF2a-IgG).…”

Section: Staurosporine Treatment Causes Increased Eif2a Phosphorylatimentioning

confidence: 99%

“…The levels of phosphorylation were significantly less than those caused by arsenite, a stress which causes marked increases in eIF2a phosphorylation in several cell types (see, e.g. 22 ).…”

Section: Staurosporine Treatment Causes Increased Eif2a Phosphorylatimentioning

confidence: 99%

Staurosporine inhibits phosphorylation of translational regulators linked to mTOR

Tee

Proud

2001

Cell Death Differ

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Treatment of Swiss 3T3 cells with staurosporine resulted in dephosphorylation of two proteins which play key roles in regulating mRNA translation. This occurred before the execution of apoptosis, assessed by caspase-3 activity. These translation regulators are p70 S6 kinase, which phosphorylates ribosomal protein S6, and eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), which both lie downstream of the mammalian target of rapamycin (mTOR). This resulted in decreased p70 S6 kinase activity, dephosphorylation of ribosomal protein S6, increased binding of 4E-BP1 to eIF4E and a concomitant decrease in eIF4F complexes. Our data show that staurosporine impairs mTOR signalling in vivo but that this not due to direct inhibition of mTOR or to inhibition of protein kinase C. It is becoming clear that agents which cause apoptosis inactivate mTOR signalling as a common early response prior to the execution of apoptosis, i.e., before caspase activation. Cell Death and Differentiation (2001) 8, 841 ± 849.

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“…These effects are achieved through three major pathways: (1) the unfolded protein response, a transcription-dependent induction of ER lumenal chaperone proteins and many other components of the secretory apparatus, which augments the polypeptide processing capacity of the ER; 5,6 (2) the activation of proteasome-dependent ER-associated degradation to remove proteins from the ER; 7,8 and (3) the control of protein translation to modulate the polypeptide traffic into the ER. 9,10 Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger apoptosis.…”

mentioning

confidence: 99%

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Boyce

Ryazanov

et al. 2008

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress has been implicated in many diseases but its cellular regulation remains poorly understood. Previously, we identified salubrinal (sal), a small molecule that protects cells from ER stressinduced apoptosis by selectively activating a subset of endogenous ER stress-signaling events. Here, we use sal as a probe in a proteomic approach to discover new information about the endogenous cellular response to ER stress. We show that sal induces phosphorylation of the translation elongation factor eukaryotic translation elongation factor 2 (eEF-2), an event that depends on eEF-2 kinase (eEF-2K). ER stress itself also induces eEF-2K-dependent eEF-2 phosphorylation, and this pathway promotes translational arrest and cell death in this context, identifying eEF-2K as a hitherto unknown regulator of ER stress-induced apoptosis. Finally, we use both sal and ER stress models to show that eEF-2 phosphorylation can be activated by at least two signaling mechanisms. Our work identifies eEF-2K as a new component of the ER stress response and underlines the utility of novel small molecules in discovering new cell biology. Cell Death and Differentiation (2008) 15, 589-599; doi:10.1038/sj.cdd.4402296; published online 11 January 2008 The endoplasmic reticulum (ER) serves as the primary processing site for membrane and secreted proteins. The ER recruits translating ribosomes, translocates newly synthesized polypeptides into its lumen, and promotes a variety of post-translational modifications and chaperone-facilitated protein folding. 1,2 Proper ER function is critical for numerous aspects of cell physiology, including vesicle trafficking, lipid and membrane biogenesis, and protein targeting and secretion. Accordingly, cells react rapidly to various forms of ER dysfunction -including the accumulation of unfolded, misfolded or excessive protein, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumenthrough a set of adaptive pathways known collectively as the ER stress response (ESR). [2][3][4][5] The ESR promotes cell survival both by increasing the capacity of the ER to fold and process client proteins and by reducing the amount of protein inside the ER. These effects are achieved through three major pathways: (1) the unfolded protein response, a transcription-dependent induction of ER lumenal chaperone proteins and many other components of the secretory apparatus, which augments the polypeptide processing capacity of the ER; 5,6 (2) the activation of proteasome-dependent ER-associated degradation to remove proteins from the ER; 7,8 and (3) the control of protein translation to modulate the polypeptide traffic into the ER. 9,10 Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger apoptosis. [11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerativ...

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Regulation of Translational Initiation during Cellular Responses to Stress

Cited by 265 publications

References 177 publications

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

Staurosporine inhibits phosphorylation of translational regulators linked to mTOR

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

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