Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability
| Autor: | Tatiana Zykova, Ann M. Bode, Weihong Wen, Wei-Ya Ma, Andria Carper, Myoung Ok Kim, Feng Zhu, C. Ho Jeong, Zigang Dong, Ke Yao, Cong Peng, Alyssa Langfald |
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| Rok vydání: | 2012 |
| Předmět: |
p53
Cancer Research DNA damage Immunoprecipitation Immunoblotting Mice Nude Apoptosis RNF2 Biology Article PcG Mice MDM2 Neoplasms Genetics Gene Knockdown Techniques Animals Humans Molecular Biology Polycomb Repressive Complex 1 Gene knockdown Cell growth Reverse Transcriptase Polymerase Chain Reaction Ubiquitination Proto-Oncogene Proteins c-mdm2 Flow Cytometry HCT116 Cells 3. Good health Cancer cell Cancer research biology.protein Mdm2 Heterografts Tumor Suppressor Protein p53 |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1 (PRC1). 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. |
| Databáze: | OpenAIRE |
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