Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes.
In normal human melanocytes various mitogens activate the mitogen-activated protein kinases ERK1/2 and the downstream transcription factor CREB (Ca2+/cAMP response element binding protein). Endothelin-1, basic fibroblast growth factor, and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation. The former two mitogens phosphorylated ERK1/2, its substrate p90rsk, and CREB. Alpha-melanotropin, forskolin, or dibutyryl cAMP failed to phosphorylate any of those targets, however. The concomitant presence of endothelin-1, basic fibroblast growth factor, and alpha-melanotropin significantly potentiated CREB phosphorylation. The mitogen-induced phosphorylation of p90rsk and CREB was dependent on ERK1/2 activation, and was mediated by intracellular calcium mobilization and by protein kinase C and tyrosine kinase activation, but not by activation of the cAMP-dependent protein kinase A. Exposure of melanocytes to ultraviolet radiation B resulted in the phosphorylation of the stress-induced mitogen- activated protein kinases p38 and JNK/SAPK, but not ERK1/2. Ultraviolet radiation B induced the phosphorylation of CREB via a pathway that was partially dependent on p38, but had no effect on p90rsk or ERK1/2. Therefore, in human melanocytes, CREB is a common downstream target for distinct effectors that are involved in either mitogenic signaling or stress signaling initiated by ultraviolet radiation B.
Tada
Akihiro
A
POLA Laboratories, Yokohama, Japan.
Pereira
Elizabeth
E
Beitner-Johnson
Dana
D
Kavanagh
Renny
R
Abdel-Malek
Zalfa A
ZA
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012016:Reference Values; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014466:Ultraviolet Rays
D017362:Cyclic AMP Response Element-Binding Protein; D008934:Mitogens; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium