Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we investigated the effects of heat treatment on melanogenesis in a mouse melanocyte cell line (Mel-Ab). It has been reported that activated extracellular signal-regulated kinase (ERK) is responsible for microphthalmia-associated transcription factor (MITF) degradation, which leads to a reduction in tyrosinase protein production and melanin synthesis. Here we demonstrate that heat treatment induces sustained ERK activation, which may inhibit melanogenesis. However, the specific ERK pathway inhibitors, PD98059 or U0126 did not restore heat-induced hypopigmentation. Furthermore, PD98059 or U0126 hardly blocked the heat-induced activation of ERK. These results suggest that heat treatment may inactivate protein phosphatase, and thus ERK activation is maintained. To support this hypothesis, we examined the effects of heat treatment on protein phosphatase 2A (PP2A) activity. The results obtained show that heat treatment inactivates PP2A, which may subsequently cause ERK activation and that heat treatment inhibits MITF promoter activity. Overall, our results demonstrate that heat treatment reduces melanin production in a temperature-dependent manner.
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PMID:Heat treatment decreases melanin synthesis via protein phosphatase 2A inactivation. 1589 74

Using B16 melanoma cells for screening, we found that a marine sponge extract has a potent anti-pigmenting effect and identified arenarol as its major active compound. In normal human melanocytes (NHMs), arenarol significantly abrogated the endothelin 1 (EDN1) stimulated expression of tyrosinase, tyrosinase-related protein 1 and dopachrome tautomerase at the transcriptional, translational and enzymatic activity (only for tyrosinase) levels. That effect was accompanied by the attenuation of the increased expression level of microphthalmia-associated transcription factor (MITF) protein at the transcriptional and translational levels. Analysis of EDN1 signaling demonstrated that arenarol significantly suppressed the EDN1-induced phosphorylation of MEK, ERK, MITF and CREB but not of Raf-1s. In contrast, the forskolin-induced phosphorylation of CREB was not down-regulated by arenarol. As for the mode of action of the suppressed phosphorylation of MEK, Raf-1 activity was not directly inhibited by arenarol in vitro and pretreatment with the protein phosphatase inhibitor okadaic acid did not affect the down-regulated phosphorylation of MEK that was induced by arenarol in NHMs. The sum of these findings suggests that arenarol abrogates the EDN1-stimulated expression of melanocyte-specific proteins by interrupting MEK phosphorylation in an as yet unknown Raf-1 inactivation mechanism.
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PMID:Arenarol isolated from a marine sponge abrogates endothelin-1-stimulated melanogenesis by interrupting MEK phosphorylation in normal human melanocytes. 2363 31

Misfolded proteins in the endoplasmic reticulum (ER) are removed through multistep processes termed ER-associated degradation (ERAD). Valosin-containing protein (VCP) plays a crucial role in ERAD as the interaction of ubiquitin fusion degradation protein 1 (Ufd1) with VCP via its SHP box motif (²²⁸F-S-G-S-G-N-R-L²³⁵) is required for ERAD. However, the mechanisms by which the VCP-Ufd1 interaction is regulated are not well understood. Here, we found that the serine 229 residue located in the Ufd1 SHP box is phosphorylated in vitro and in vivo by cyclic adenosine monophosphate-dependent protein kinase A (PKA), with this process being enhanced by either forskolin (an adenylyl cyclase activator) or calyculin A (a protein phosphatase inhibitor). Moreover, a phosphomimetic mutant (S229D) of Ufd1 as well as treatment by forskolin, calyculin A, or activated PKA strongly reduced Ufd1 binding affinity for VCP. Consistent with this, the Ufd1 S229D mutant significantly inhibited ERAD leading to the accumulation of ERAD substrates such as a tyrosinase mutant (C89R) and 3-hydroxy-3-methylglutaryl coenzyme A reductase. However, a non-phosphorylatable Ufd1 mutant (S229A) retained VCP-binding ability and was less effective in blocking ERAD. Collectively, our results support that Ufd1 S229 phosphorylation status mediated by PKA serves as a key regulatory point for the VCP-Ufd1 interaction and functional ERAD.
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PMID:Ufd1 phosphorylation at serine 229 negatively regulates endoplasmic reticulum-associated degradation by inhibiting the interaction of Ufd1 with VCP. 3147 23

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