Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability

RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1. RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here, we show that knockdown of RNF2 significantly inhibits both cell proliferation and c...

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Bibliographic Details
Published in:	Oncogene Vol. 33; no. 4; pp. 421 - 428
Main Authors:	Wen, W, Peng, C, Kim, M O, Ho Jeong, C, Zhu, F, Yao, K, Zykova, T, Ma, W, Carper, A, Langfald, A, Bode, A M, Dong, Z
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-01-2014 Nature Publishing Group
Subjects:	631/67/395 631/80/458/582 631/80/82/23 631/80/86 Animals Apoptosis Apoptosis - physiology Cell Biology Epigenetics Flow Cytometry Gene expression Gene Knockdown Techniques Gene mutations Genetic aspects Genetic regulation Genetic research HCT116 Cells Heterografts Human Genetics Humans Identification and classification Immunoblotting Immunoprecipitation Internal Medicine Medicine Medicine & Public Health Mice Mice, Nude Neoplasms - genetics Neoplasms - metabolism Oncology original-article Polycomb Repressive Complex 1 - genetics Polycomb Repressive Complex 1 - metabolism Proto-Oncogene Proteins c-mdm2 - metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Protein p53 - metabolism Tumors Ubiquitination MDM2 PcG ubiquitination RNF2 p53
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Summary:	RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1. RNF2 is highly expressed in many tumors, suggesting that it might have an oncogenic function, but the mechanism is unknown. Here, we show that knockdown of RNF2 significantly inhibits both cell proliferation and colony formation in soft agar, and induces apoptosis in cancer cells. Knockdown of RNF2 in HCT116 p53 +/+ cells resulted in significantly more apoptosis than was observed in RNF2 knockdown HCT116 p53 −/− cells, indicating that RNF2 knockdown-induced apoptosis is partially dependent on p53. Various p53-targeted genes were increased in RNF2 knockdown cells. Further studies revealed that in RNF2 knockdown cells, the p53 protein level was increased, the half-life of p53 was prolonged and p53 ubiquitination was decreased. In contrast, cells overexpressing RNF2 showed a decreased p53 protein level, a shorter p53 half-life and increased p53 ubiquitination. Importantly, we found that RNF2 directly binds with both p53 and MDM2 and promotes MDM2-mediated p53 ubiquitination. RNF2 overexpression could also increase the half-life of MDM2 and inhibit its ubiquitination. The regulation on p53 and MDM2 stability by RNF2 was also observed during the etoposide-induced DNA damage response. These results provide a possible mechanism explaining the oncogenic function of RNF2, and because RNF2 is important for cancer cell survival and proliferation, it might be an ideal target for cancer therapy or prevention.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Present address is State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an, China 710032
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2012.605