p38 regulates pigmentation via proteasomal degradation of tyrosinase.
The synthesis of melanin pigments, or melanogenesis, is regulated by the balance of a variety of signal transduction pathways. Among these pathways, p38 MAPK signaling was found to be involved in stress-induced melanogenesis and to be activated by alpha-melanocyte-stimulating hormone (alpha-MSH) and ultraviolet irradiation. Previous studies have shown that alpha-MSH-stimulated melanogenesis can be inhibited by blocking p38 MAPK activity with SB203580, a pyridinyl imidazole compound. Consistent with this, we observed that pyridinyl imidazoles (SB203580 and SB202190) inhibited both basal and alpha-MSH-induced melanogenesis in B16 melanoma cells. However, SB202474, which has no ability to inhibit p38 MAPK activity and is usually used as a negative control compound in p38 MAPK studies, also suppressed melanin synthesis induction. Furthermore, the independence of the p38 kinase pathway from the repression of melanogenesis by pyridinyl imidazole compounds was also confirmed by small interfering RNA experiments. Interfering with p38 MAPK expression surprisingly stimulated melanogenesis and tyrosinase family protein expression. Although the molecular mechanism(s) by which p38 promotes the degradation of melanogenic enzymes remain to be determined, the involvement of the ubiquitin-proteasome pathway was demonstrated by co-treatment with the proteasome-specific inhibitor MG132 and the relative decrease in the ubiquitination of tyrosinase in cells transfected with p38-specific small interfering RNA.
Bellei
Barbara
B
Laboratory of Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IRCCS, 00144 Rome, Italy.
Maresca
Vittoria
V
Flori
Enrica
E
Pitisci
Angela
A
Larue
Lionel
L
Picardo
Mauro
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism; D004795:Enzyme Stability; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008543:Melanins / Q000096:biosynthesis / Q000235:genetics; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism*; D010858:Pigmentation / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D011725:Pyridines; D034741:RNA, Small Interfering; D057149:Ubiquitinated Proteins; D000521:alpha-MSH; D014442:Monophenol Monooxygenase; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole