From JNK to Pay Dirt: Jun Kinases, their Biochemistry, Physiology and Clinical Importance (original) (raw)
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Genes & Development, 1993
The activity of c-Jun is regulated by phosphorylation. Various stimuli including transforming oncogenes and UV light, induce phosphorylation of serines 63 and 73 in the amino-terminal activation domain of c-Jun and thereby potentiate its trans-activation function. We identified a serine/threonine kinase whose activity is stimulated by the same signals that stimulate the amino-terminal phosphorylation of c-Jun. This novel c-Jun amino-terminal kinase (JNK), whose major form is 46 kD, binds to a specific region within the c-Jun trans-activation domain and phosphorylates serines 63 and 73. Phosphorylation results in dissociation of the c-Jun-JNK complex. Mutations that disrupt the kinase-binding site attenuate the response of c-Jun to Ha-Ras and UV. Therefore the binding of JNK to c-Jun is of regulatory importance and suggests a mechanism through which protein kinase cascades can specifically modulate the activity of distinct nuclear targets.
Photochemistry and Photobiology, 2000
We have previously demonstrated that the oxidizing component of ultraviolet-A (UVA) plays a central role in the activation of the nuclear oncogene and transcription factor, c-fos, in cultured human skin fibroblasts. We have now shown that expression of both c-jun and c-fos (AP-1) family of transcription factors is modulated by short and long wavelength solar ultraviolet (UV) radiation in human fibroblasts and human KB cells. UVA radiation activated c-jun and c-fos in both fibroblasts and KB cells, whereas ultraviolet-B (UVB) radiation activates such oncogenes only in KB cells. Moreover, decreasing the intracellular levels of reducing equivalents in human fibroblasts by glutathione (GSH) depletion lowered the UVA dose threshold for c-jun and c-fos activation several-fold and greatly amplified the UVA-mediated activation of such genes. A more modest effect was observed in GSHdepleted KB cells. In both GSH-depleted fibroblasts and KB cells, UVB radiation failed to amplify c-jun and c-fos activation indicating that the oxidative component of UVB plays a minor role in the modulation of such oncogene expression. These findings clearly indicate that both c-jun and c-fos are activated by the oxidizing component of UVA radiation in human fibroblasts and KB cells, while UVB-mediated modulation seems to be restricted to human epithelial cells and does not involve oxidizing intermediates.
RapidandPreferential Activation ofthec-junGeneduring the Mammalian UV Response
1991
Exposure ofmammalian cells toDNA-damaging agents leads toactivation ofagenetic responseknownasthe UV response.Because several previously identified UV-inducible genescontain AP-1binding sites within their promoters, we investigated theinduction ofAP-1activity byDNA-damaging agents. We foundthatexpression ofbothc-jun andc-fos, whichencode proteins thatparticipate information oftheAP-1complex, israpidly induced bytwodifferent DNA-damaging agents: UV andH202.Interestingly, thec-jun gene isfarmore responsive toUV thanany other immediate-early genethat was examined, including c-fos. Other junandfos geneswereonlymarginally affected byUV orH202.Furthermore, UVisamuchmore efficient inducer ofc-jun thanphorbol esters, thestandard inducers ofc-jun expression. Thispreferential responseofthec-jun gene is mediated byits5'control region andrequires theTPA responseelement, suggesting thatthiselement also servesasanearly target forthesignal transduction pathway elicited byDNA damage. BothUV an...
Activation of c-Jun-NH2-Kinase by UV Irradiation Is Dependent on p21
Journal of Biological Chemistry, 1996
We have demonstrated previously that Jun-NH 2-kinase (JNK) activation in vitro is potentiated by association with the p21 ras protein. To determine if in vivo activation of JNK also depends on p21 ras , we have used M1311 cells that carry the cDNA for the neutralizing antibody to p21 ras , Y13-259, under a dexamethasone-inducible promoter. The ability of UV to activate JNK gradually decreased over a 4-day period of cell growth in dexamethasone. This decrease coincides with weaker transcriptional activation measured via gel shift and chloramphenicol acetyltransferase assays. Peptides corresponding to amino acids 96-110 on p21 ras , which were shown to block Ras-JNK association, inhibited UV-mediated JNK activation in mouse fibroblast 3T3-4A cells as well as in M1311 cells, further supporting the role of p21 ras in UV-mediated JNK activation. Overall, the present studies provide in vivo confirmation of the role p21 ras plays in JNK activation by UV irradiation.
Differential Regulation of the AP-1 Family Members by UV Irradiation In Vitro and In Vivo
Cellular Signalling, 1998
We have examined the effect of UVB and solar-simulated irradiation on the expression of the AP-1 family of transcription factors and the cytokine IL-6 both in cell cultures and in human skin in vivo. UVB irradiation potently induced c-jun, junB and c-fos mRNA levels in vitro in HaCaT cells. IL-6 mRNA was induced in response to UVB irradiation 2-3 h later than c-jun, junB and c-fos mRNAs. In human skin in vivo, solar-simulated irradiation induced transiently junB expression. Genistein, a tyrosine kinase inhibitor, augmented the induction of c-jun and junB by UVB irradiation in HaCaT cells. The results of this study provide evidence that in addition to c-jun and c-fos, junB is also an essential component of the human UV-response. This study also suggests that UVB irradiation regulates the AP-1 family by several mechanisms and that the signalling mechanisms of UVB irradiation are considerably different from the ones used by UVC irradiation. cell signal 10; 3:191-195, 1998.
Activation of c-Jun-NH2-kinase by UV irradiation is dependent on p21ras
1996
We have demonstrated previously that Jun-NH 2-kinase (JNK) activation in vitro is potentiated by association with the p21 ras protein. To determine if in vivo activation of JNK also depends on p21 ras , we have used M1311 cells that carry the cDNA for the neutralizing antibody to p21 ras , Y13-259, under a dexamethasone-inducible promoter. The ability of UV to activate JNK gradually decreased over a 4-day period of cell growth in dexamethasone. This decrease coincides with weaker transcriptional activation measured via gel shift and chloramphenicol acetyltransferase assays. Peptides corresponding to amino acids 96-110 on p21 ras , which were shown to block Ras-JNK association, inhibited UV-mediated JNK activation in mouse fibroblast 3T3-4A cells as well as in M1311 cells, further supporting the role of p21 ras in UV-mediated JNK activation. Overall, the present studies provide in vivo confirmation of the role p21 ras plays in JNK activation by UV irradiation.
Molecular and cellular biology, 1999
Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases is an early response of cells upon exposure to DNA-damaging agents. JNK-mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulation of JNK1 activity is not a general early response of cells exposed to genotoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as with methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs such as mafosfamide, mitomycin C, N-hydroxyethyl-N-chloroethylnitrosourea, and treosulfan did not elicit this response. The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2). To inv...
Phosphorylation of c-Fos by Members of the p38 MAPK Family: ROLE IN THE AP-1 RESPONSE TO UV LIGHT
Journal of Biological Chemistry, 2005
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 AP1driven gene transcription regulation.