Phosphorylation of c-Fos by Members of the p38 MAPK Family

Abstract

Exposure to sources of UV radiation, such as sunlight, induces a number of cellular alterations that are highly dependent on its ability to affect gene expression. Among them, the rapid activation of genes coding for two subfamilies of proto-oncoproteins, Fos and Jun, which constitute the AP-1 transcription factor, plays a key role in the subsequent regulation of expression of genes involved in DNA repair, cell proliferation, cell cycle arrest, death by apoptosis, and tissue and extracellular matrix remodeling proteases. Besides being regulated at the transcriptional level, Jun and Fos transcriptional activities are also regulated by phosphorylation as a result of the activation of intracellular signaling cascades. In this regard, the phosphorylation of c-Jun by UV-induced JNK has been readily documented, whereas a role for Fos proteins in UV-mediated responses and the identification of Fosactivating kinases has remained elusive. Here we identify p38 MAPKs as proteins that can associate with c-Fos and phosphorylate its transactivation domain both in vitro and in vivo. This phosphorylation is transduced into changes in its transcriptional ability as p38-activated c-Fos enhances AP1-driven gene expression. Our findings indicate that as a consequence of the activation of stress pathways induced by UV light, endogenous c-Fos becomes a substrate of p38 MAPKs and, for the first time, provide evidence that support a critical role for p38 MAPKs in mediating stress-induced c-Fos phosphorylation and gene transcription activation. Using a specific pharmacological inhibitor for p38␣ and -␤, we found that most likely these two isoforms mediate UV-induced c-Fos phosphorylation in vivo. Thus, these newly described pathways act concomitantly with the activation of c-Jun by JNK/ MAPKs, thereby contributing to the complexity of AP1-driven gene transcription regulation.Repeated and prolonged exposure to sunlight and hence to UV radiation causes skin damage that may induce alterations in the DNA and ultimately evolve into skin cancer. Extensive investigation of the response of mammalian cells to UV light has shown that exposure to UV light results in the rapid activation of a group of enzymes known as stress-activated protein kinases (SAPKs) 1 (1, 2) and the induction of expression of a set of immediate early genes (ergs) (3-6), which in turn participate in the cellular responses to this type of environmental stress.SAPKs is the common denomination for a subgroup of highly homologous proteins, JNKs and p38s, that belong to a superfamily of serine-threonine kinases known as mitogen-activated protein kinases (MAPKs) (7-10). These kinases play an essential role in the transduction of environmental stimuli to the nucleus, as they are capable of regulating the expression of genes involved in a variety of cellular processes, including cell proliferation, differentiation, programmed cell death, and neoplastic transformation (11-13). MAPKs have been classified into at least six subfamilies, among which the Erk/MAPKs (Erk1 and -2), JNKs (JN...

GSK‐3β‐dependent destabilization of cyclin D1 mediates replicational stress‐induced arrest of cell cycle

“…Thus, GSK-3b appears to be an arbiter of cell fate towards proliferation, arrest or apoptosis. Further, it would also be interesting to investigate the role of P38 in stress signaling already known to induce c-Fos phosphorylation and gene trans-activation following UV stress [30] and to characterize the molecules that facilitate cross-talk between checkpoint kinases and mitogenic signaling under genotoxic stress. In fact a recent report suggests that ATR can transiently activate GSK-3b following UV irradiation [31].…”

Regulation of Xylosyltransferase I Gene Expression by Interleukin 1β in Human Primary Chondrocyte Cells

“…Activation of XT-I promoter by p38 signaling pathways is probably due to phosphorylation of c-Fos by p38 MAPKs. Indeed, it has been shown that p38 MAPKs are able to activate c-Fos (42,43). Thus, this pathway acts concomitantly with the activation of c-Jun by JNK/MAPK, thereby contributing to the complexity of AP-1 driven XT-I gene transcription regulation.…”

Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor

“…Coincidently, vGPCR-induced p38␣ phosphorylates and induces the transcriptional activity of Hif-1␣, a hypoxia-inducible factor that regulates the expression of the vegf promoter (40). In addition, p38␣ regulates AP-1 transcriptional activity (61), and this transcription factor also controls vGPCR-driven vegf promoter activity (15,24). Interestingly, very recent studies have shown that STAT3 is required by vGPCR to induce transformation (62) and by several other oncogenes to induce VEGF secretion (63).…”