p38 Regulates Pigmentation via Proteasomal Degradation of Tyrosinase
p38 Regulates Pigmentation via Proteasomal Degradation of Tyrosinase
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DOI：
10.1074/jbc.m109.070573
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发表时间：
2010-03-05
影响因子：
4.8
通讯作者：
Picardo, Mauro
中科院分区：
文献类型：
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作者：
Bellei, Barbara;Maresca, Vittoria;Picardo, Mauro
黑色素的合成或黑素生成受多种信号转导途径的平衡调节。在这些途径中，p38 MAPK信号被发现参与应激诱导的黑素生成，并被α-黑素细胞刺激激素（α-MSH）和紫外线照射激活。先前的研究表明，α-MSH刺激的黑素生成可以通过用SB 203580（一种吡啶基咪唑化合物）阻断p38 MAPK活性来抑制。与此一致，我们观察到吡啶基咪唑（SB 203580和SB 202190）抑制B16黑色素瘤细胞中的基础和α-MSH诱导的黑素生成。然而，SB 202474，其没有抑制p38 MAPK活性的能力，并且通常在p38 MAPK研究中用作阴性对照化合物，也抑制黑色素合成诱导。此外，独立的p38激酶途径的抑制黑素生成的吡啶基咪唑化合物也证实了小干扰RNA实验。干扰p38 MAPK表达令人惊讶地刺激黑素生成和酪氨酸酶家族蛋白表达。尽管p38促进黑素生成酶降解的分子机制仍有待确定，但通过与蛋白酶体特异性抑制剂MG 132共处理以及用p38特异性小干扰RNA转染的细胞中酪氨酸酶泛素化的相对减少证明了泛素-蛋白酶体途径的参与。
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.