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Heterochromatin protein 1alpha: a hallmark of cell proliferation relevant to clinical oncology.

ABSTRACT: Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1alpha, beta and gamma, which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1alpha shows a proliferation-dependent regulation, which neither HP1beta nor gamma display. During transient cell cycle exit, the HP1alpha mRNA and protein levels diminish. Transient depletion of HP1alpha, but not HP1beta or gamma, in tumoural and primary human cells leads to defects in chromosome segregation. Notably, analysis of an annotated collection of samples derived from carcinomas reveals an overexpression of HP1alpha mRNA and protein, which correlates with clinical data and disease outcome. Our results unveil a specific expression pattern for the HP1alpha isoform, suggesting a unique function related to cell division and tumour growth. The overexpression of HP1alpha constitutes a new example of a potential epigenetic contribution to tumourigenesis that is of clinical interest for cancer prognosis.

SUBMITTER: De Koning L

PROVIDER: S-EPMC3378125 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Heterochromatin protein 1alpha: a hallmark of cell proliferation relevant to clinical oncology.

De Koning Leanne L Savignoni Alexia A Boumendil Charlène C Rehman Haniya H Asselain Bernard B Sastre-Garau Xavier X Almouzni Geneviève G

EMBO molecular medicine 20090601 3

Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1alpha, beta and gamma, which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1alpha shows a proliferation-dependent regulation, which neither HP1beta nor gam ...[more]

PMID: 20049717

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Project description:BackgroundLamins are major structural proteins of the nucleus and contribute to the organization of various nuclear functions. Mutations in the human lamin A gene cause a number of highly degenerative diseases, collectively termed as laminopathies. Cells expressing lamin mutations exhibit abnormal nuclear morphology and altered heterochromatin organization; however, the mechanisms responsible for these defects are not well understood.Methodology and principal findingsThe lamin A rod domain mutants G232E, Q294P and R386K are either diffusely distributed or form large aggregates in the nucleoplasm, resulting in aberrant nuclear morphology in various cell types. We examined the effects of these lamin mutants on the distribution of heterochromatin protein 1 (HP1) isoforms. HeLa cells expressing these mutants showed a heterogeneous pattern of HP1alpha and beta depletion but without altering HP1gamma levels. Changes in HP1alpha and beta were not observed in cells expressing wild-type lamin A or mutant R482L, which assembled normally at the nuclear rim. Treatment with proteasomal inhibitors led to restoration of levels of HP1 isoforms and also resulted in stable association of lamin mutants with the nuclear periphery, rim localization of the inner nuclear membrane lamin-binding protein emerin and partial improvement of nuclear morphology. A comparison of the stability of HP1 isoforms indicated that HP1alpha and beta displayed increased turnover and higher basal levels of ubiquitination than HP1gamma. Transcript analysis of components of the ubiquitination pathway showed that a specific F-box protein, FBXW10 was induced several-fold in cells expressing lamin mutants. Importantly, ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels.ConclusionsMislocalized lamins can induce ubiquitin-mediated proteasomal degradation of certain HP1 isoforms by activation of FBXW10, a member of the F-box family of proteins that is involved in E3 ubiquitin ligase activity.

Dataset Information

Heterochromatin protein 1alpha: a hallmark of cell proliferation relevant to clinical oncology.

Publications

Heterochromatin protein 1alpha: a hallmark of cell proliferation relevant to clinical oncology.

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