JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes

Abstract

JHDM1B is an evolutionarily conserved and ubiquitously expressed member of the JHDM (JmjC-domain-containing histone demethylase) family. Because it contains an F-box motif, this protein is also known as FBXL10 (ref. 4). With the use of a genome-wide RNAi screen, the JHDM1B worm orthologue (T26A5.5) was identified as a gene that regulates growth. In the mouse, four independent screens have identified JHDM1B as a putative tumour suppressor by retroviral insertion analysis. Here we identify human JHDM1B as a nucleolar protein and show that JHDM1B preferentially binds the transcribed region of ribosomal DNA to repress the transcription of ribosomal RNA genes. We also show that repression of ribosomal RNA genes by JHDM1B is dependent on its JmjC domain, which is necessary for the specific demethylation of trimethylated lysine 4 on histone H3 in the nucleolus. In agreement with the notion that ribosomal RNA synthesis and cell growth are coupled processes, we show a JmjC-domain-dependent negative effect of JHDM1B on cell size and cell proliferation. Because aberrant ribosome biogenesis and the disruption of epigenetic control mechanisms contribute to cellular transformation, these results, together with the low levels of JHDM1B expression found in aggressive brain tumours, suggest a role for JHDM1B in cancer development.

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

“…F-box proteins function as components of SCF-type E3 ubiquitin ligase complexes and may participate in co-repressor complexes (Gearhart et al 2006). The presence of a histone demethylase activity in FBXL10 was shown to be important for regulation of cell senescence and transcription of rRNAs (Jin et al 2004, Takeuchi et al 2006, Frescas et al 2007, He et al 2008, Pfau et al 2008, Yamagishi et al 2008. In our experiments, truncated versions of FBXL10 gene were recovered lacking the 5 0 -terminal part encoding the demethylase domain.…”

A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas

“…Mutations that inactivate the tumor-suppressive activities of RB or p53 can result in aberrant upregulation of essential components of protein synthesis machinery and increase ribosome biogenesis, further leading to enhanced mRNA translation rates (28). JHDM1A and JHDM1B directly bind to rDNA promoter and repress the transcription of rRNA genes through epigenetic mechanisms (37,38). Moreover, some zinc finger proteins such as ZFP37, ZNF274, and JAZ are located and function in the nucleolus (39)(40)(41).…”

Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process

“…A genome-wide screen of 44 MoMuLVinduced T cell lymphomas for novel targets of proviral DNA integration yielded clones of 149 independent provirus integrations. Six of these integrations, cloned from five independent tumors, had targeted a gene we named Ndy1, also known as FBXL10 or JHDM1B (9,10,16,17). Two of them were cloned from a single tumor, D0, suggesting that this tumor consists of at least two populations of cells, both of which carry an inte-grated provirus in this locus.…”

“…Ndy1 encodes a protein that contains a JmjC domain (9,10,16,17), a CXXC zinc finger, a PHD zinc finger, a proline-rich region (PRR), an F-box, and a leucine-rich repeat (LRR) (Fig. 1 A and ref.…”