Journal Article

Involvement of ERKs, RSK2 and PKR in UVA-induced signal transduction toward phosphorylation of eIF2α (Ser<sup>51</sup>)

Tatyana A. Zykova, Feng Zhu, Yiguo Zhang, Ann M. Bode and Zigang Dong

in Carcinogenesis

Volume 28, issue 7, pages 1543-1551
Published in print July 2007 | ISSN: 0143-3334
Published online April 2007 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgm070
Involvement of ERKs, RSK2 and PKR in UVA-induced signal transduction toward phosphorylation of eIF2α (Ser51)

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Double-stranded RNA-dependent protein kinase R (PKR) has been implicated in anti-viral (antitumor) and apoptotic responses. PKR is activated by extracellular stresses and phosphorylates the α subunit of protein synthesis initiation factor eIF2, thereby inhibiting protein synthesis and impeding virus multiplication. Phosphorylation of eIF2α in mammalian cells has been shown to be increased after ultraviolet (UV) stress and to be required for UV-induced repression of protein translation. UVA is an important etiological factor in skin carcinogenesis and we observed that UVA induced phosphorylation of PKR (Thr451) and eIF2α (Ser51) in mouse skin epidermal JB6 Cl41 cells. The induction was suppressed by the MEK1 inhibitor, PD 98059. UVA stimulation of PKR and eIF2α phosphorylation was also inhibited by a dominant-negative mutant (DNM) of ERK2- or RSK2-deficient cells (RSK2). An inhibitor of p38, SB 202190 or a DNM of p38α kinase (DNM-p38α) suppressed UVA-induced phosphorylation of eIF2α (Ser51) but had no effect on phosphorylation of PKR (Thr451). Our data indicated that phosphorylation of PKR at Thr451 is mediated through ERK2 and RSK2, but not through p38 kinase, and is involved in the regulation of Ser51 phosphorylation of eIF2α in UVA-irradiated JB6 cells. In vitro and in vivo kinase assays indicated that phosphorylation of eIF2α at Ser51 occurred indirectly through ERK2, RSK2 or p38 kinase in the cellular response to UVA. These data may lead to the use of these signaling molecules as targets to develop more effective chemopreventive agents with fewer side effects to control UV-induced skin cancer.

Journal Article.  6405 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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