Increased Histone H1 Phosphorylation and Relaxed Chromatin Structure in Rb-Deficient Fibroblasts

Fibroblasts derived from embryos homozygous for a disruption of the retinoblastoma gene (Rb) exhibit a shorter G$_{1}$ than their wild-type counterparts, apparently due to highly elevated levels of cyclin E protein and deregulated cyclin-dependent kinase 2 (CDK2) activity. Here we demonstrate that t...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1996-10, Vol.93 (21), p.11510-11515
Main Authors: Herrera, Rafael E., Chen, Feng, Weinberg, Robert A.
Format: Article
Language:English
Subjects:
Biochemistry
CDC2-CDC28 Kinases
Cell Cycle
Cell Division
Cell Line
Cell nucleus
Chromatin
Chromatin - physiology
Chromatin - ultrastructure
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases - metabolism
Cyclins
Diploidy
Embryo, Mammalian
Embryos
Fibroblasts
Genes
Genes, Retinoblastoma
Histones
Histones - chemistry
Histones - isolation & purification
Histones - metabolism
Homozygote
Humans
Interphase
Micrococcal Nuclease
Peptide Mapping
Phosphopeptides - chemistry
Phosphopeptides - isolation & purification
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Retinoblastoma Protein - deficiency
Thymidine - metabolism
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Summary:Fibroblasts derived from embryos homozygous for a disruption of the retinoblastoma gene (Rb) exhibit a shorter G$_{1}$ than their wild-type counterparts, apparently due to highly elevated levels of cyclin E protein and deregulated cyclin-dependent kinase 2 (CDK2) activity. Here we demonstrate that the Rb$^{-/-}$ fibroblasts display higher levels of phosphorylated H1 throughout G$_{1}$ with the maximum being 10-fold higher than that of the Rb$^{+/+}$ fibroblasts. This profile of intracellular H1 phosphorylation corresponds with deregulated CDK2 activity observed in in vitro assays, suggesting that CDK2 may be directly responsible for the in vivo phosphorylation of H1. H1 phosphorylation has been proposed to lead to a relaxation of chromatin structure due to a decreased affinity of this protein for chromatin after phosphorylation. In accord with this, chromatin from the Rb$^{-/-}$ cells is more susceptible to micrococcal nuclease digestion than that from Rb$^{+/+}$ fibroblasts. Increased H1 phosphorylation and relaxed chromatin structure have also been observed in cells expressing several oncogenes, suggesting a common mechanism in oncogene and tumor suppressor gene function.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.93.21.11510