Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with <i>Ink4a</i> Deletion

Calés, Carmela; Román-Trufero, Mónica; Pavón, Leticia; Serrano, Iván Castelló; Melgar, Teresa; Endoh, Mitsuhiro; Pérez, Cirilo; Koseki, Haruhiko; Vidal, Miguel

doi:10.1128/mcb.01136-07

Cited by 86 publications

(91 citation statements)

References 75 publications

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“…However, the mechanism of Rnf2 in cancer development remains poorly understood. Previously, Rnf2 was shown to repress the transcription of p16Ink4a, which mediates Rnf2 activities in cancer cells 22,33,34). However, in the present study, Rnf2 directly degraded p53 through the proteasome pathway.…”

Section: Discussioncontrasting

confidence: 46%

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

Fang

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Large numbers of studies have focused on the posttranslational regulation of p53 activity. One of the best-known negative regulators for p53 is MDM2, an E3 ubiquitin ligase that promotes p53 degradation through proteasome degradation pathways. Additional E3 ligases have also been reported to negatively regulate p53. However, whether these E3 ligases have distinct/overlapping roles in the regulation of p53 is largely unknown. In this study, we identify RNF2 (ring finger protein 2) as an E3 ligase that targets p53 for degradation. The E3 ligase activity of RNF2 requires Bmi1 protein, a component of the polycomb group (PcG) complex. The up-regulation of p53 does not affect RNF2 expression. Unlike Mdm2, RNF2 only degrades p53 in selective cell lines, such as those from germ-cell tumors. The knockdown of RNF2 induces apoptosis, which can be rescued through the reduction of p53 expression. Moreover, the down-regulation of RNF2 expression in germ-cell tumors significantly reduces tumor cell growth, while the simultaneous down-regulation of both genes restores tumor cell growth in vitro and in tumor xenograft models. Furthermore, a reverse correlation between RNF2 and p53 expression was detected in human ovarian cancer tissues. Together, these results indicate that RNF2 is an E3 ligase for p53 degradation in selective cells, implicating RNF2 as a therapeutic target to restore tumor suppression through p53 in certain tumor cells.

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Section: Discussioncontrasting

confidence: 46%

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

Fang

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…(Jacobs et al, 1999;Itahana et al, 2003;Gil et al, 2004;Dietrich et al, 2007;Maertens et al, 2009). Interestingly, polycomb group proteins are also essential for stem cell self-renewal in both mice and humans (Lessard and Sauvageau, 2003;Molofsky et al, 2003;Park et al, 2003;Cales et al, 2008), and this is in part due to their ability to bind and repress the INK4A-ARF locus.…”

Section: Transcriptional Regulation Of the Ink4a-arf Locusmentioning

confidence: 99%

Transcriptional regulation of cellular senescence

2011

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“…The contribution of PcG proteins to stem cells was indicated by genome-wide profiling of their chromatin binding and H3K27 methylation in ES cells (4) and was further supported by genetic evidence. Findings obtained from mice or ES cells deficient in Rae28, Bmi1, and Ring1B suggested that PcG complex 1 is crucially involved in HSCs (5)(6)(7)(8), neural stem cells (9), ES cells (10), and further leukemic stem cells (11). Impaired control of p16 cyclin-dependent kinase inhibitor (p16CKI), p19ARF (7,12), p21 (13), and E4F1 (14) expression was reported to be at least in part responsible for stem cell defects in Bmi1-deficient mice.…”

mentioning

confidence: 99%

Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity

Ohtsubo

Yasunaga

Ohno

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Polycomb-group (PcG) genes encode multimeric nuclear protein complexes, PcG complex 1 and 2. PcG complex 2 was proved to induce transcription repression and to further methylate histone H3 at lysine-27 (H3K27). Subsequently PcG complex 1 is recruited through recognition of methylated H3K27 and maintains the transcription silencing by mediating monoubiquitination of histone H2A at lysine-119. Genetic evidence demonstrated a crucial role for PcG complex 1 in stem cells, and Bmi1, a member of PcG complex 1, was shown to sustain adult stem cells through direct repression of the INK4a locus encoding cyclin-dependent kinase inhibitor, p16CKI, and p19ARF. The molecular functions of PcG complex 1, however, remain insufficiently understood. In our study, deficiency of Rae28, a member of PcG complex 1, was found to impair ubiquitin-proteasome-mediated degradation of Geminin, an inhibitor of DNA replication licensing factor Cdt1, and to increase protein stability. The resultant accumulation of Geminin, based on evidence from retroviral transduction experiments, presumably eliminated hematopoietic stem cell activity in Rae28-deficient mice. Rae28 mediates recruiting Scmh1, which provides PcG complex 1 an interaction domain for Geminin. Moreover, PcG complex 1 acts as the E3 ubiquitin ligase for Geminin, as we demonstrated in vivo as well as in vitro by using purified recombinant PcG complex 1 reconstituted in insect cells. Our findings suggest that PcG complex 1 supports the activity of hematopoietic stem cells, in which high-level Geminin expression induces quiescence securing genome stability, by enhancing cycling capability and hematopoietic activity through direct regulation of Geminin.Rae28 ͉ Scmh1 ͉ HSCs ͉ ubiquitination ͉ DNA replication licensing

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Inactivation of the Polycomb Group Protein Ring1B Unveils an Antiproliferative Role in Hematopoietic Cell Expansion and Cooperation with Tumorigenesis Associated with Ink4a Deletion

Cited by 86 publications

References 75 publications

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

Transcriptional regulation of cellular senescence

Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity

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