CDK inhibitors selectively diminish cell cycle controlled activation of the histone H4 gene promoter by p220NPAT and HiNF-P

Partha Mitra, Prachi N. Ghule, Margaretha Van Der Deen, Ricardo Medina, Rong Lin Xie, William F. Holmes, Xin Ye, Keiichi I. Nakayama, J. Wade Harper, Janet L. Stein, Gary S. Stein, Andre J. Van Wijnen

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Cell cycle progression into S phase requires the induction of histone gene expression to package newly synthesized DNA as chromatin. Cyclin E stimulation of CDK2 at the Restriction point late in G1 controls both histone gene expression by the p220NPAT/HiNF-P pathway and initiation of DNA replication through the pRB/E2F pathway. The three CDK inhibitors (CKIs) p21CIP1/WAF1, p27KIP1, and p57KIP2 attenuate CDK2 activity. Here we find that g-irradiation induces p21CIP1/WAF1 but not the other two CKIs, while reducing histone H4 mRNA levels but not histone H4 gene promoter activation by the p220NPAT/HiNF-P complex. We also show that p21CIP1/WAF1 is less effective than p27 KIP1 and p57KIP2 in inhibiting the CDK2 dependent phosphorylation of p220NPAT at subnuclear foci and transcriptional activation of histone H4 genes. The greater effectiveness of p57KIP2 in blocking the p220NPAT/HiNF-P pathway is attributable in part to its ability to form a specific complex with p220NPAT that may suppress CDK2/cyclin E phosphorylation through direct substrate inhibition. We conclude that CKIs selectively control stimulation of the histone H4 gene promoter by the p220NPAT/HiNF-P complex.

Original languageEnglish (US)
Pages (from-to)438-448
Number of pages11
JournalJournal of Cellular Physiology
Volume219
Issue number2
DOIs
StatePublished - May 1 2009

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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    Mitra, P., Ghule, P. N., Van Der Deen, M., Medina, R., Xie, R. L., Holmes, W. F., Ye, X., Nakayama, K. I., Harper, J. W., Stein, J. L., Stein, G. S., & Van Wijnen, A. J. (2009). CDK inhibitors selectively diminish cell cycle controlled activation of the histone H4 gene promoter by p220NPAT and HiNF-P. Journal of Cellular Physiology, 219(2), 438-448. https://doi.org/10.1002/jcp.21687