Expression of the Double-Stranded RNA-Dependent Protein Kinase (p68) in Squamous Cell Carcinoma of the Head and Neck Region

Haines, G. Kenneth; Becker, S.; Ghadge, Ghanashaym; Kies, Merrill S.; Pelzer, Harold J.; Radosevich, James A.

doi:10.1001/archotol.1993.01880220098012

Cited by 30 publications

(17 citation statements)

References 27 publications

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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%

“…This and accumulating evidence have now implicated PKR as a potential tumor suppressor gene; however, increased levels of an active form of PKR have been observed in a broad range of human cancers, including squamous carcinoma of the head and neck (Haines et al, 1993a(Haines et al, ,b, 1998, lung carcinomas (Haines et al, 1992) colonicadenocarcinoma (Singh et al, 1997) and breast carcinoma (Haines et al, 1996). Thus, the regulation and activation of PKR in transformed cells is still an enigma.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Deregulation of E2F-1 has the potential not only to drive cells into apoptosis but, depending on their state of differentiation and development, to induce cellular proliferation. It is interesting that there is evidence in the literature that PKR status may be an important regulator of tumorigenesis and that increased levels of PKR in lung and colon cancers are associated with improved survival (Haines et al, 1993;Jagus et al, 1999). We are currently investigating whether the PKR-induced disturbance of the orchestrated balance between E2F-1-induced cell-cycle progression and eIF-2a-induced protein synthesis downregulation is the missing link that explains why Ad5E2F-treated cells ultimately undergo apoptosis.…”

Section: E2f-1 Pkr Stainingmentioning

confidence: 99%

Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis

et al. 2002

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The transcription factor E2F-1 induces cell cycle progression at the G1/S checkpoint, and deregulation of E2F-1 provokes apoptosis in a wide variety of malignant cells. To date only p14 ARF and p73, a p53 homologue, have been identified as E2F-1-inducible genes capable of mediating an apoptotic response. Here we show that adenovirus-mediated E2F-1 overexpression in cancer cells induces expression and autophosphorylation of the double-stranded RNA-dependent protein kinase PKR leading to phosphorylation of its downstream target, the a-subunit of the eukaryotic translation initiation factor 2 (eIF-2a) and to apoptotic cell death. This PKR-dependent apoptosis occurs in cell lines with mutated p53 and in cell lines with mutated p53 and p73, and is significantly reduced by the chemical inhibition of PKR activation. Further, PKR 7/7 mouse embryo fibroblasts, but not PKR +/+ mouse embryo fibroblasts, demonstrate significant resistance to E2F-1-induced apoptosis. We conclude that an important pathway of E2F-1-mediated apoptosis is dependent on PKR activation and does not require p53 or p73.

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“…In mice, three PKR transcripts with tissue-specific differential expression have been described, but their molecular basis and functional significance remain unresolved (160,188). Expression of PKR varies in a timeand tissue-specific manner during human fetal development; levels are imperceptible in blastema and immature mesenchymal cells but high in a variety of more differentiated tissues such as epithelial cells (141). In adult tissues, PKR levels are low in the proliferating immature zone of squamous mucosa and increase progressively in the nonproliferating mature keratinocytes (141).…”

Section: Introductionmentioning

confidence: 99%

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

García

Gil

Ventoso

et al. 2006

Microbiol Mol Biol Rev

703

731

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SUMMARY The double-stranded RNA-dependent protein kinase PKR is a critical mediator of the antiproliferative and antiviral effects exerted by interferons. Not only is PKR an effector molecule on the cellular response to double-stranded RNA, but it also integrates signals in response to Toll-like receptor activation, growth factors, and diverse cellular stresses. In this review, we provide a detailed picture on how signaling downstream of PKR unfolds and what are the ultimate consequences for the cell fate. PKR activation affects both transcription and translation. PKR phosphorylation of the alpha subunit of eukaryotic initiation factor 2 results in a blockade on translation initiation. However, PKR cannot avoid the translation of some cellular and viral mRNAs bearing special features in their 5′ untranslated regions. In addition, PKR affects diverse transcriptional factors such as interferon regulatory factor 1, STATs, p53, activating transcription factor 3, and NF-κB. In particular, how PKR triggers a cascade of events involving IKK phosphorylation of IκB and NF-κB nuclear translocation has been intensively studied. At the cellular and organism levels PKR exerts antiproliferative effects, and it is a key antiviral agent. A point of convergence in both effects is that PKR activation results in apoptosis induction. The extent and strength of the antiviral action of PKR are clearly understood by the findings that unrelated viral proteins of animal viruses have evolved to inhibit PKR action by using diverse strategies. The case for the pathological consequences of the antiproliferative action of PKR is less understood, but therapeutic strategies aimed at targeting PKR are beginning to offer promising results.

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Expression of the Double-Stranded RNA-Dependent Protein Kinase (p68) in Squamous Cell Carcinoma of the Head and Neck Region

Cited by 30 publications

References 27 publications

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

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

Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

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