Activation of the Mitf promoter by lipid‐stimulated activation of p38‐stress signalling to CREB
2006
The microphthalmia-associated transcription factor
Mitf plays a critical role in regulating many aspects
of melanocyte biology. It is required for melanoblast
and postnatal melanocyte survival, regulates proliferation,
and activates genes associated with differentiation
such as tyrosinase and related genes
involved in melanogenesis. Identifying the signals
that regulate Mitf expression is crucial if we are to
understand how cells of the melanocyte lineage
respond to environmental cues. Here we show that
the Mitf promoter is induced by lipid signalling via
the p38 stress-activated kinase pathway that is also
activated by a wide range of receptors as well as
UV irradiation. Signalling via p38 leads to increased
phosphorylation and activation of cyclic adenosine
monophosphate response element-binding (CREB)
that binds and activates the Mitf promoter via the
cyclic adenosine monophosphate (cAMP) response
element. Moreover, we also show that activation of
p38 mediated by lipids is potentiated by inhibition
of the PI3kinase pathway but not by inhibition of
protein kinase A (PKA). The results identify a mechanism
in which stress signalling via p38 leads to
activation of CREB, enhanced Mitf expression and
consequently increased tyrosinase expression. The
results are relevant for the regulation of melanocytes
by Mitf, but also raise the possibility that lipid
mediated activation of p38 signalling may represent
a potential therapy for vitiligo.
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