CDK inhibitors selectively diminish cell cycle controlled activation of the histone H4 gene promoter by p220NPAT and HiNF-P
✍ Scribed by 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
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 593 KB
- Volume
- 219
- Category
- Article
- ISSN
- 0021-9541
No coin nor oath required. For personal study only.
✦ Synopsis
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 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.