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The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b).

ABSTRACT: The Ink4a-Arf-Ink4b locus has a crucial role in both cellular senescence and tumorigenesis. JmjC domain-containing histone demethylase 1b (Jhdm1b, also known as Kdm2b and Fbxl10), the mammalian paralog of the histone demethylase Jhdm1a (also known as Kdm2a and Fbxl11), has been implicated in cell-cycle regulation and tumorigenesis. In this report, we show that Jhdm1b is a histone H3 lysine 36 (H3K36) demethylase. Knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferation and induces cellular senescence in a pRb- and p53 pathway-dependent manner. Notably, the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through derepression of p15(Ink4b), as loss of p15(Ink4b) function rescues cell-proliferation defects in Jhdm1b-knockdown cells. Chromatin immunoprecipitation on ectopically expressed Jhdm1b demonstrates that Jhdm1b targets the p15(Ink4b) locus and regulates its expression in an enzymatic activity-dependent manner. Alteration of Jhdm1b level affects Ras-induced neoplastic transformation. Collectively, our results indicate that Jhdm1b is an H3K36 demethylase that regulates cell proliferation and senescence through p15(Ink4b).

SUBMITTER: He J

PROVIDER: S-EPMC2612995 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b).

He Jin J Kallin Eric M EM Tsukada Yu-Ichi Y Zhang Yi Y

Nature structural & molecular biology 20081005 11

The Ink4a-Arf-Ink4b locus has a crucial role in both cellular senescence and tumorigenesis. JmjC domain-containing histone demethylase 1b (Jhdm1b, also known as Kdm2b and Fbxl10), the mammalian paralog of the histone demethylase Jhdm1a (also known as Kdm2a and Fbxl11), has been implicated in cell-cycle regulation and tumorigenesis. In this report, we show that Jhdm1b is a histone H3 lysine 36 (H3K36) demethylase. Knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferat ...[more]

PMID: 18836456

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Project description:Background/aimActivin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs).MethodsCell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied.ResultsNUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity.ConclusionsOur studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.

Dataset Information

The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b).

Publications

The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b).

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