Mitogen- and stress-activated protein kinase 1 is critical for interleukin-1-induced, CREB-mediated, c-fos gene expression in keratinocytes.
c-fos, which encodes a transcription factor of the AP-1 family, is a prototypical immediate-early gene induced by a number of proinflammatory cytokines including interleukin-1 (IL-1), the latter being an important regulator of skin homeostasis. Using the human keratinocyte cell line HaCaT as an in vitro model, we dissected the molecular pathways leading to IL-1-induced c-fos gene induction. Phosphorylation of the transcription factor cAMP response element binding protein (CREB) at Ser133 was found to be essential for IL-1-induced c-fos gene induction and was closely paralleled by protein kinase A (PKA) activation. In contrast to other cell types, the cyclooxygenase/prostaglandin pathway, known to activate the cAMP/PKA cascade, plays little, if any, role in c-fos expression downstream of the IL-1 receptor in keratinocytes. Simultaneous activation of several of the mitogen-activated protein kinase (MAPK) cascades occurred in response to IL-1, but each differentially contributed to c-fos induction by IL-1, with the p38/MAPK being the most crucial of all, the extracellular signal-regulated kinase pathway contributing in an additive manner and the Jun N-terminal kinase pathway playing little, if any, role. We also demonstrate that p38-dependent activation of mitogen- and stress-activated kinase 1 (MSK1), a CREB kinase, is a key step for c-fos gene activation by IL-1. Finally, we identify MSK1 as playing a positive role in the control of cell proliferation of both HaCaT keratinocytes and the A431 human epidermoid carcinoma line.
INSERM U697, Hôpital Saint-Louis, Paris, France.
M
M
Schiller
M
M
Böhm
S
S
Dennler
J M
JM
Ehrchen
A
A
Mauviel
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D015603:Keratinocytes / Q000201:enzymology* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; D016760:Proto-Oncogene Proteins c-fos; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1