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J. Biol. Chem., Vol. 276, Issue 43, 40225-40233, October 26, 2001
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From the Dipartimento di Sanitá Pubblica e Biologia
Cellulare, Sezione di Anatomia, Universita' degli Studi di Roma Tor
Vergata, via O. Raimondo 8, 00173 Rome, Italy
In vitro addition of stem
cell factor (SCF) to c-kit-expressing A1-A4
spermatogonia from prepuberal mice stimulates their progression into
the mitotic cell cycle and significantly reduces apoptosis in these
cells. SCF addition results in a transient activation of extracellular
signal-regulated kinases (Erk)1/2 as well as of phosphatidylinositol
3-kinase (PI3K)-dependent Akt kinase. These events are
followed by a rapid re-distribution of cyclin D3, which becomes
predominantly nuclear, whereas its total cellular amount does not
change. Nuclear accumulation of cyclin D3 is coupled to transient
activation of the associated kinase activity, assayed using the
retinoblastoma protein (Rb) as a substrate. These events were followed
by a transient accumulation of cyclin E, stimulation of the associated
histone H1-kinase activity, a delayed accumulation of cyclin A2, and Rb
hyper-phosphorylation. All the events associated with SCF-induced cell
cycle progression are inhibited by the addition of either a PI3K
inhibitor or a mitogen-activated protein-kinase kinase (MEK) inhibitor,
indicating that both MEK and PI3K are essential for c-kit-mediated
proliferative response. On the contrary, the anti-apoptotic effect of
SCF is not influenced by the separate addition of either MEK or PI3K inhibitors. Thus, SCF effects on mitogenesis and survival in c-kit expressing spermatogonia rely on different signal transduction pathways.
Signaling through Extracellular Signal-regulated
Kinase Is Required for Spermatogonial Proliferative Response to
Stem Cell Factor*
*
This work was supported by grants from Ministero
dell'Universita' e della Ricerca Scientifica e Tecnologica and from
Agenzia Spaziale Italiana.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.: 39-06-72596272;
Fax: 39-06-72596268; E-mail:
pellegrino.rossi@med.uniroma2.it.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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