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CDK inhibitors selectively diminish cell cycle controlled activation of the histone H4 gene promoter by p220 NPAT and HiNF‐P
Author(s) -
Mitra Partha,
Ghule Prachi N.,
van der Deen Margaretha,
Medina Ricardo,
Xie Ronglin,
Holmes William F.,
Ye Xin,
Nakayama Keiichi I.,
Harper J. Wade,
Stein Janet L.,
Stein Gary S.,
van Wijnen Andre J.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21687
Subject(s) - histone , chemistry , cyclin dependent kinase , microbiology and biotechnology , cyclin dependent kinase 2 , biology , cell cycle , gene , biochemistry
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 p220 NPAT /HiNF‐P pathway and initiation of DNA replication through the pRB/E2F pathway. The three CDK inhibitors (CKIs) p21 CIP1/WAF1 , p27 KIP1 , and p57 KIP2 attenuate CDK2 activity. Here we find that γ‐irradiation induces p21 CIP1/WAF1 but not the other two CKIs, while reducing histone H4 mRNA levels but not histone H4 gene promoter activation by the p220 NPAT /HiNF‐P complex. We also show that p21 CIP1/WAF1 is less effective than p27 KIP1 and p57 KIP2 in inhibiting the CDK2 dependent phosphorylation of p220 NPAT at subnuclear foci and transcriptional activation of histone H4 genes. The greater effectiveness of p57 KIP2 in blocking the p220 NPAT /HiNF‐P pathway is attributable in part to its ability to form a specific complex with p220 NPAT 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 p220 NPAT /HiNF‐P complex. J. Cell. Physiol. 219: 438–448, 2009. © 2009 Wiley‐Liss, Inc.