Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR

Kim, Steve; Forman, Adam P; Mathews, Michael B.; Gunnery, Shobha

doi:10.1038/sj.onc.1203632

Cited by 105 publications

(118 citation statements)

References 37 publications

(34 reference statements)

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“…The MAC16 tumour also shows elevated autophosphorylation of PKR and phosphorylation of eIF2a, which has been linked to constitutive activation of NF-kB and chemoresistance (unpublished). Other studies have also shown an increased autophosphorylation of PKR and phosphorylation of eIF2a in human breast carcinoma cell lines, compared with nontransformed epithelial cells (Kim et al, 2000), and in human melanoma cells compared with nontransformed melanocytes in culture (Kim et al, 2002). In addition analysis of colon cancer specimens showed that transformation from normal mucosa to adenomas and carcinomas coincided with an increase in PKR expression (Kim et al, 2002).…”

Section: Discussionmentioning

confidence: 87%

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

et al. 2007

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Previous studies suggest that the activation (autophosphorylation) of dsRNA-dependent protein kinase (PKR) can stimulate protein degradation, and depress protein synthesis in skeletal muscle through phosphorylation of the translation initiation factor 2 (eIF2) on the a-subunit. To understand whether these mediators are important in muscle wasting in cancer patients, levels of the phospho forms of PKR and eIF2a have been determined in rectus abdominus muscle of weight losing patients with oesophago-gastric cancer, in comparison with healthy controls. Levels of both phospho PKR and phospho eIF2a were significantly enhanced in muscle of cancer patients with weight loss irrespective of the amount and there was a linear relationship between phosphorylation of PKR and phosphorylation of eIF2a (correlation coefficient 0.76, P ¼ 0.005). This suggests that phosphorylation of PKR led to phosphorylation of eIF2a. Myosin levels decreased as the weight loss increased, and there was a linear relationship between myosin expression and the extent of phosphorylation of eIF2a (correlation coefficient 0.77, P ¼ 0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients.

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Section: Discussionmentioning

confidence: 87%

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

et al. 2007

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“…The presented pro®les were obtained in one out of ®ve independently repeated experiments that gave similar results events that link the inactivation of eIF2a to the proapoptotic activity of the enzyme is not well understood. Moreover, unexpectedly, an active form of PKR is highly and constitutively expressed in a variety of human cancers (Haines et al, 1993a(Haines et al, ,b, 1998Kim et al, 2000;Singh et al, 1997). One might think of several possible explanations for this enigma.…”

Section: Discussionmentioning

confidence: 99%

Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells

et al. 2001

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The interferon (IFN)-induced, double stranded RNA (dsRNA)-activated serine/threonine kinase, PKR, is a potent negative regulator of cell growth when overexpressed in yeast or mammalian cells. Paradoxically, while it can function as a tumor suppressor and inducer of apoptosis, it is overexpressed in a variety of human cancers. To resolve this enigma, we established cell-lines that overexpress PKR in non-transformed and in v-mos transformed CHO cells. Overexpression of PKR suppressed the proliferation of CHO cells by inducing a transient G0/G1 arrest, followed by a delayed G2/M arrest, which attenuated cell cycle progression. These e ects were accompanied by early induction of p21/ WAF-1 and delayed downregulation of CDC2 and cyclin B1. Induction of proapoptotic activity of the ectopic PKR paralleled the onset of G2/M arrest in CHO cells. However, while transiently inducing p21/WAF-1, PKR did not impose G2/M arrest or apoptosis in v-mostransformed cells, nor was CDC2 or cyclin B1 downregulated in those cells. These ®ndings link the proapoptotic activity of PKR to the arrest of cell cycle at the G2/M phase. Consequently, the apoptotic activity of PKR could be counter-acted by an oncogene-like vmos that overrides the G2/M arrest induced by PKR. Oncogene (2001) 20, 8045 ± 8056.

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“…Histograms represent the mean value of the ratio of cleaved caspase-3 to actin after normalization to the ratio of lane 2 for the indicated lanes from four independent experiments (n ¼ 4). Statistical significance of the difference as calculated by Student's t-test is with *Po0.006, **Po0.04 arm was found to be compromised in malignant breast tumor cells due to upregulation of the guanine nucleotide exchange factor eIF2B, 31 which antagonizes the inhibitory effects of phosphorylated eIF2a on protein synthesis. 32 Interestingly, increased eIF2B levels were observed in various transformed cells and accounted for the high tolerance of these cells to Figure 5 PKR induces JNK phosphorylation in response to doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it was previously shown that human invasive ductal breast carcinomas and several human breast tumor cell lines contain elevated levels of PKR compared with non-malignant breast cells. 30,31 However, the PKR-eIF2a phosphorylation SubG1: 64% SubG1: 44% Figure 4 Phosphorylation of eIF2a protects cells from doxorubicin-induced death. (a) eIF2a S/S and eIF2a A/A MEFs were left untreated (con) or treated with 1 mM doxorubicin (dox) for the indicated time periods.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the a-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2a phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2a kinases and the biological role of eIF2a phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2a kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2a phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2a phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2a phosphorylation. The eukaryotic cell has established intricate mechanisms to cope with environmental stress. It does so by changing protein expression in a manner that promotes adaptation to the assaulting stress. Protein expression within the cell is regulated at the transcriptional, translational and posttranslational levels. Translational control is often used under conditions of cellular stress because it allows immediate and selective changes in protein levels. 1 Translation itself is divided into three distinct phases: initiation, elongation and termination. By far the most explored step is that of initiation, which has been shown to be regulated by different extracellular stimuli. 1 One of the major pathways that control translation initiation is that of the phosphorylation of the a-subunit of translation initiation factor eIF2. 2 Phosphorylation of eIF2a at serine 51 (S51) leads to the inhibition of global protein synthesis providing the cell with the opportunity to elicit adaptive responses not only by saving energy but also by preventing the accumulation of unwanted proteins that could interfere with cellular functions. 1 There are four eIF2a kinases that share a homologous kinase domain (KD) but possess different regulatory domains that enable them to become activated by distinct stimuli. 2 The eIF2a kinases are the heme-regulated inhibitor, which is found mainly in erythroid cells and is activated by heme deficiency; the endoplasmic reticulum (ER)-resident kinase (PERK), which is activated by ER stress and inhibits protein synthesis as part of the unfolded protein response; the general aminoacid nonderepressing kinase 2 (GCN2), which responds to amino-acid deprivation and becomes activated by uncharged tRNA and the RNA-dependent protein kinase PKR, an interfer...

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Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR

Cited by 105 publications

References 37 publications

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

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