The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b

Jin He, Eric M. Kallin, Yu Ichi Tsukada, Yi Zhang

Research output: Contribution to journalArticlepeer-review

213 Citations (Scopus)

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 p15Ink4b, as loss of p15Ink4b function rescues cell-proliferation defects in Jhdm1b-knockdown cells. Chromatin immunoprecipitation on ectopically expressed Jhdm1b demonstrates that Jhdm1b targets the p15Ink4b 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 p15Ink4b.

Original languageEnglish
Pages (from-to)1169-1175
Number of pages7
JournalNature Structural and Molecular Biology
Volume15
Issue number11
DOIs
Publication statusPublished - Nov 27 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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