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PMID:19170105

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Citation

Mitra, P, Ghule, PN, van der Deen, M, Medina, R, Xie, RL, Holmes, WF, Ye, X, Nakayama, KI, Harper, JW, Stein, JL, Stein, GS and van Wijnen, AJ (2009) CDK inhibitors selectively diminish cell cycle controlled activation of the histone H4 gene promoter by p220NPAT and HiNF-P. J. Cell. Physiol. 219:438-48

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 gamma-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.

Links

PubMed PMC2981436 Online version:10.1002/jcp.21687

Keywords

Animals; Cell Cycle/physiology; Cell Cycle/radiation effects; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Line/radiation effects; Cyclin E/genetics; Cyclin E/metabolism; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/metabolism; Cyclin-Dependent Kinase Inhibitor p57/genetics; Cyclin-Dependent Kinase Inhibitor p57/metabolism; Cyclin-Dependent Kinases/antagonists & inhibitors; Cyclin-Dependent Kinases/metabolism; Gamma Rays; Gene Expression Regulation; Genes, Reporter; Histones/genetics; Histones/metabolism; Humans; Mice; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Promoter Regions, Genetic; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Repressor Proteins/genetics; Repressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CDN1B

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CDN1B

involved_in

GO:0033673: negative regulation of kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CDN1C

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CDN1C

involved_in

GO:0033673: negative regulation of kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CDN1C

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CDN1C

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q9BQA5

P

Seeded From UniProt

complete

HUMAN:CDN1C

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14207

F

Seeded From UniProt

complete

MOUSE:CDN1C

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NPAT

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49918

F

Seeded From UniProt

complete

HUMAN:NPAT

located_in

GO:0015030: Cajal body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NPAT

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HINFP

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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