Role of p38 mitogen-activated protein kinase (p38 MAPK) in cytokine-induced rat islet cell apoptosis 1 1Abbreviations: IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; CREB, cAMP-responsive element-binding protein; iNOS, inducible nitric oxide synthase; ATF-2, activating transcription factor-2; STAT, signal transducer and activator of transcription; and MSK, mitogen- and stress-activated protein kinase.

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

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Mitogen-activated protein kinase-dependent and -independent routes control shedding of transmembrane growth factors through multiple secretases

Biochemical Journal ◽

10.1042/bj3630211 ◽

2002 ◽

Vol 363 (2) ◽

pp. 211-221 ◽

Cited By ~ 17

Author(s):

Juan Carlos MONTERO ◽

Laura YUSTE ◽

Elena DÍAZ-RODRÍGUEZ ◽

Azucena ESPARÍS-OGANDO ◽

Atanasio PANDIELLA

Keyword(s):

Growth Factors ◽

Protein Kinase ◽

Uv Light ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Mitogen Activated Protein Kinase ◽

Ovary Cells ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Factor Α

Solubilization of a number of membrane proteins occurs by the action of cell-surface proteases, termed secretases. Recently, the activity of these secretases has been reported to be controlled by the extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and the p38 mitogen-activated protein kinase (MAPK) routes. In the present paper, we show that shedding of membrane-anchored growth factors (MAGFs) may also occur through MAPK-independent routes. In Chinese-hamster ovary cells, cleavage induced by protein kinase C (PKC) stimulation was largely insensitive to inhibitors of the ERK1/ERK2 and p38 routes. Other reagents such as sorbitol or UV light stimulated MAGF cleavage independent of PKC. The action of sorbitol on cleavage was only partially prevented by the combined action of inhibitors of the p38 and ERK1/ERK2 routes, indicating that sorbitol can also stimulate shedding by MAPK-dependent and -independent routes. Studies in cells devoid of activity of the secretase tumour necrosis factor-α-converting enzyme (TACE) indicated that this protease had an essential role in PKC- and ERK1/ERK2-mediated shedding. However, secretases other than TACE may also cleave MAGFs since sorbitol could still induce shedding in these cells. These observations suggest that cleavage of MAGFs is a complex process in which multiple secretases, activated through different MAPK-dependent and -independent routes, are involved.

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