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

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 Fos-activating 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 p38α and -β, 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. 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 Fos-activating 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 p38α and -β, 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) 1The abbreviations used are: SAPK, stress-activated kinase; AP-1, activator protein 1; GFP, green fluorescent protein; MAPK, mitogen-activated kinases; AU5, epitope tag peptide, AU5; HA, epitope tag peptide hemagglutinin; GST, glutathione S-transferase; JNK, c-Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; MAPKKs, MAPK kinases; MEK, MAPK/ERK kinase; MOPS, 4-morpholinepropanesulfonic acid; DTT, dithiothreitol; PMSF, phenylmethylsulfonyl fluoride; PBS, phosphate-buffered saline; wt, wild type; TAD, transcriptional activation domain; FL, full-length; mut, mutant. (1Dent P. Yacoub A. Contessa J. 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PubMed Scopus Google Scholar). cells with and in DTT, and PMSF, and with for and by proteins to with in by for at with the of of these as epitope and with to with protein by to the of JNK and p38 kinases Cell on and with expression with of and of the of DNA with in Cell to a and and activities the the as by the cells on and by as described cells with PBS, and with and in for with PBS, cells with and with as for cells with and with the with in with and a with the of in the of of p38 we the and the on an UV cells and the and the cells in a UV with and the cells to the for the cells in and to and with UV light and with the as in and in of DTT, on of of and for for in a in of DTT, and at for on a for and the and at protein protein of protein at with of and of DNA in of DTT, PMSF, for a and with and used as to the for an on in at at of to the to the of the for Cell and its as described for the the by with as to both and to as protein to the by with the of the for in we the which of a a that a This can at is to at proteins by can a of a for to the and on and cell cells expression to the and with that proteins and p38 for of the and with been described A. 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Neoplasia (Bratisl.). 2003; 5: 319-329Crossref PubMed Google Scholar, R.J. Cell. PubMed Scopus Google Scholar). In of we the in phosphorylation of c-Fos FL, cells to UV cells with c-Fos by exposure to UV light and at by by an that the exposure of cells to UV light induced a phosphorylation of c-Fos as by a of this protein that and at results the cells with and the with an In to that the changes in c-Fos to we with the serine-threonine of UV exposure by that the induced by this stress is a consequence of the of on on the c-Fos protein these that c-Fos is a of phosphorylation induced by cellular stress. UV c-Fos in SAPKs of the p38 of we to the role of in the pathways that to UV-induced c-Fos of the that at of UV light induced on c-Fos and Thus, we cells with with the of p38α JNK, and we the phosphorylation of c-Fos in cell by an of p38 which the of UV light on the of c-Fos of whereas JNK and with the results of the of the in the c-Fos protein the of MAPK phosphorylation the of by a and that the induced in c-Fos to phosphorylation by p38 MAPKs in of these cells with a c-Fos that has these key to with the UV in the of by the c-Fos this which that changes in c-Fos to the of these MAPK These results indicate that this most likely to phosphorylation by UV p38 the activation of SAPKs in these cells we the by an capable of the of isoforms an that these kinases by UV light expression of the kinases an These results indicate most the p38 MAPKs JNK can involved in stress-induced c-Fos phosphorylation on specific and In of the role of the in UV-induced c-Fos we used an and we the in cells in which endogenous p38 signaling is by a specific p38 pharmacological L. 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Genes Dev. 2001; PubMed Scopus Google Scholar). shown in c-Fos in the of UV a to the this UV-induced cells with these indicate that c-Fos is a substrate of the isoforms of p38 kinases and on this phosphorylation to to the as the result of activation induced by UV UV-induced p38 and UV radiation results in c-Fos phosphorylation and we to the of this in UV-induced on AP-1 with cells with the to UV shown in of with cells in the of an as UV light induced a as by the of a of and which by with the inhibitor the of c-Fos in these we cells with an the of c-Fos which in the of a of to the these that in cells by UV light, is and this is dependent on p38 and a critical role for p38α in mediating stress-induced c-Fos and gene transcription activation in response to UV c-Fos for p38 the role of phosphorylation on the c-Fos transactivation and the of the MAPK on we to the of of the to this these we a of c-Fos to phosphorylation the of by these proteins as in and used as for in vitro p38 a of of protein used in the in c-Fos phosphorylation by -β, and MAPK are c-Fos which with the that this cells are to UV light and with to this to induce phosphorylation on a as the c-Fos in to that to the that on the TAD, that this may a for these kinases in the the phosphorylation of and by p38α whereas kinases a that the that in the to also with in the c-Fos by p38α and -β, and phosphorylation induced by These results that can in vitro with by a set of p38 a of and MAPK on the c-Fos to the in vitro phosphorylation of MAPK the c-Fos by is we the of in c-Fos transcriptional in the cells with the as with the p38 kinases and that MAPK transcriptional activation of the which is with the that the c-Fos is in at a the transcriptional of c-Fos in response to of the p38 These indicate that the that can in on the TAD, are to phosphorylation and transcriptional of early genes is a common to the cellular response to both and cellular the of expression of of the AP-1 transcription such as c-Jun and has been shown to the exposure of cells to UV light M. 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UV p38α and are in the they with found in the and with c-Fos UV whereas with c-Fos in the in the that -β, and to the and remained may also to the in the c-Fos transactivation as by the can this to c-Fos transcriptional activation the protein to the This also to can c-Fos as most likely the also c-Fos in the This is are p38 are also that that they may specific K. J. Cell. Signal. PubMed Scopus Google Scholar). This is by the that p38 isoforms on transcription the regulation of c-Jun R. S. J. G. J. 2003; PubMed Scopus Google Scholar). the phosphorylation of c-Fos in response to pathways and the of of the p38 by JNK, indicate that p38 kinases can mediate this In with of cells with the p38 inhibitor L. S. S. PubMed Scopus Google Scholar) the UV-induced and AP-1 whereas the inhibitor F. 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