Signaling through extracellular signal-regulated kinase is required for spermatogonial proliferative response to stem cell factor.
In vitro addition of stem cell factor (SCF) to c-kit-expressing A(1)-A(4) 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.
Dolci
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S
Dipartimento di Sanitá Pubblica e Biologia Cellulare, Sezione di Anatomia, Universita' degli Studi di Roma Tor Vergata, via O. Raimondo 8, 00173 Rome, Italy.
Pellegrini
M
M
Di Agostino
S
S
Geremia
R
R
Rossi
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D016193:G1 Phase; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D016196:S Phase; D015398:Signal Transduction; D013093:Spermatogonia / Q000166:cytology* / Q000187:drug effects*; D019089:Stem Cell Factor / Q000494:pharmacology*
D019925:Cyclin A; D056743:Cyclin D3; D016213:Cyclins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D019089:Stem Cell Factor; C534697:Ccnd3 protein, mouse; C503689:Ccne2 protein, mouse