Title

The histone gene activator HINFP is a nonredundant cyclin E/CDK2 effector during early embryonic cell cycles

UMMS Affiliation

Department of Cancer Biology; Department of Cell Biology

Date

7-11-2009

Document Type

Article

Subjects

Animals; Blastocyst; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cells, Cultured; Cyclin E; Cyclin-Dependent Kinase 2; Embryo, Mammalian; Female; Fibroblasts; G1 Phase; Gene Expression Regulation, Developmental; Histones; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; S Phase; Signal Transduction; Time Factors

Disciplines

Cancer Biology | Cell Biology | Life Sciences | Medicine and Health Sciences

Abstract

Competency for DNA replication is functionally coupled to the activation of histone gene expression at the onset of S phase to form chromatin. Human histone nuclear factor P (HiNF-P; gene symbol HINFP) bound to its cyclin E/cyclin-dependent kinase 2 (CDK2) responsive coactivator p220(NPAT) is a key regulator of multiple human histone H4 genes that encode a major subunit of the nucleosome. Induction of the histone H4 transcription factor (HINFP)/p220(NPAT) coactivation complex occurs in parallel with the CDK-dependent release of pRB from E2F at the restriction point. Here, we show that the downstream CDK-dependent cell cycle effector HINFP is genetically required and, in contrast to the CDK2/cyclin E complex, cannot be compensated. We constructed a mouse Hinfp-null mutation and found that heterozygous Hinfp mice survive, indicating that 1 allele suffices for embryogenesis. Homozygous loss-of-function causes embryonic lethality: No homozygous Hinfp-null mice are obtained at or beyond embryonic day (E) 6.5. In blastocyst cultures, Hinfp-null embryos exhibit a delay in hatching, abnormal growth, and loss of histone H4 gene expression. Our data indicate that the CDK2/cyclin E/p220(NPAT)/HINFP/histone gene signaling pathway at the G1/S phase transition is an essential, nonredundant cell cycle regulatory mechanism that is established early in embryogenesis.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12359-64. Epub 2009 Jul 9. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

19590016