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J. Biol. Chem., Vol. 275, Issue 52, 41011-41017, December 29, 2000
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From the MAPKs are crucially involved in the regulation of
growth and differentiation of a variety of cells. To elucidate the role of MAPKs in keratinocyte differentiation, activation of ERK, JNK, and
p38 in response to stimulation with extracellular calcium was analyzed.
We provide evidence that calcium-induced differentiation of
keratinocytes is associated with rapid and transient activation of the
Raf/MEK/ERK pathway. Stimulation of keratinocytes with extracellular
calcium resulted in activation of Raf isozymes and their downstream
effector ERK within 10-15 min, but did not increase JNK or p38
activity. Calcium-induced ERK activation differed in kinetics from
mitogenic ERK activation by epidermal growth factor and could be
modulated by alterations of intracellular calcium levels.
Interestingly, calcium stimulation led to down-regulation of Ras
activity at the same time that ERK activation was initiated. Expression
of a dominant-negative mutant of Ras also did not significantly impair
calcium-induced ERK activation, indicating that calcium-mediated ERK
activation does not require active Ras. Despite the transient nature of
ERK activation, calcium-induced expression of the
cyclin-dependent kinase inhibitor p21/Cip1 and the
differentiation marker involucrin was sensitive to MEK inhibition,
which suggests a role for the Raf/MEK/ERK pathway in early stages of
keratinocyte differentiation.
Ras-independent Activation of the Raf/MEK/ERK Pathway upon
Calcium-induced Differentiation of Keratinocytes*
,¶,,, and
Institut für Medizinische
Strahlenkunde und Zellforschung (MSZ), University of Würzburg,
Versbacher Strasse 5 and the § Klinik und Poliklinik
für Haut- und Geschlechtskrankheiten, University of
Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany
*
This work was supported by Grant LU 477/3-2 (to S. L. and
M. G.) through Program "Molekulare Differenzierungsmechanismen von Epithelien" (SPP1028) from the Deutsche Forschungsgemeinschaft.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
49-931-201-3851; Fax: 49-931-201-3835; E-mail:
s.ludwig@mail.uni-wuerzburg.de.
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