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Journal of Neuroscience, Vol 15, 6200-6212, Copyright © 1995 by Society for Neuroscience
NGF regulates the PC12 cell cycle machinery through specific inhibition of the Cdk kinases and induction of cyclin D1
GZ Yan and EB Ziff
Howard Hughes Medical Institute, Department of Biochemistry, New York University Medical Center, New York 10016, USA.
We have examined the effects of NGF on components of the PC12 cell cycle
machinery. We show that NGF represses over 6-8 d the levels of specific cdk
kinase proteins and the G2-M phase specific cyclin B1 and the S phase
marker PCNA as well as the level of phosphorylation of the retinoblastoma
(Rb) protein. All of these changes may provide a basis for a NGF block to
cell cycling. Unexpectedly, the G1 phase-specific cyclin D1 was
dramatically increased by inducers of differentiation (NGF and FGF), but
not by inducers of proliferation (EGF and insulin). Although the levels of
cyclin D1/cdk2 and cyclin D1/cdk4 complexes increased following NGF
treatment, as did cyclin D1/Rb complexes, the associated kinase activities
declined, indicating that NGF also induces an inhibitor of cdk kinase
activity. In agreement, NGF induced the cdk inhibitory protein, p21, which
was found in cyclin D1/cdk kinase complexes after NGF treatment. We show
that vector over expression of cyclin D1 in PC12 is sufficient on its own
to arrest the cells in G1 phase and inhibit expression of PCNA. These
results indicate that NGF induction of cyclin D1 and inactivation of cdk
kinases, the latter possibly by increase of p21, play a central role in the
NGF block of PC12 cell cycling.
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