Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability

Wen, Weihong; Peng, Cong; Kim, M. O.; Jeong, Chul Ho; Zhu, Feng; Yao, Ke; Зыкова, Т. А.; Ma, Weiya; Carper, Andria; Langfald, Alyssa; Bode, Ann M.; Dong, Zigang

doi:10.1038/onc.2012.605

Cited by 51 publications

(46 citation statements)

References 29 publications

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“…Contrastingly, another polycomb complex protein RNF2, also known as Ring1B/Ring2 is seen to bind with both p53 and MDM2 in colon cancer cell lines and promote MDM2-mediated p53 ubiquitination. RNF2 overexpression also increases the half-life of MDM2 and inhibits its ubiquitination[118],[119]. These observations indicate that polycomb proteins play important roles in p53/MDM2 regulation and may present novel targets for cancer therapy or prevention.…”

Section: Modulators Of the Mdm2-p53 Pathwaymentioning

confidence: 79%

The MDM2-p53 pathway revisited

Nag¹,

Qin²,

et al. 2013

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The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.

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Section: Modulators Of the Mdm2-p53 Pathwaymentioning

confidence: 79%

The MDM2-p53 pathway revisited

Nag¹,

Qin²,

et al. 2013

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“…The MDM2-p53-negative feedback controls p53 signaling at proper range with respect to cell stress [10], [11]. Besides a few direct E3 ligases targeting p53, more and more E3 ligases are found to modulate MDM2-p53 complex, such as RNF31 and RNF2 [12], [13].…”

Section: Introductionmentioning

confidence: 99%

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Yang

Wang

et al. 2017

Neoplasia

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The ubiquitin binding protein SHAPRIN is highly expressed in human breast cancer, one of the most frequent female malignancies worldwide. Here, we perform SHARPIN depletion in breast cancer cells together with RNA sequencing. The global expression profiling showed p53 signaling as a potential SHARPIN target. SHARPIN depletion decreased cell proliferation, which effect could be rescue by p53 knocking down. Depletion SHARPIN significantly increases p53 protein level and its target genes in multiple breast cancer cell lines. Further experiment revealed that SHARPIN could facilitate p53 poly-ubiquitination and degradation in MDM2 dependent manner. Immuno-precipitation assay showed that SHARPIN associated with MDM2 and prolonged MDM2 protein stability. Analysis of public available database showed SHARPIN correlated with poor prognosis specifically in p53 wild-type breast cancer patients. Together, our finding revealed a novel modifier for p53/MDM2 complex and suggested SHARPIN as a promising target to restore p53 function in breast cancer.

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“…A recent study has shown that the knockdown of Rnf2 significantly inhibits cell proliferation and colony formation in the colon cancer HCT116 cell line (31). In addition, it was also associated with induction of apoptosis by regulating MDM2 and p53 stability (31). Similarly, Su et al (9) reported that Rnf2 is essential for the proliferation of ovarian and testicular cancer cells by functioning as an E3 ligase for p53 degradation.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells

et al. 2017

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Abstract. Rnf2 is a fundamental component of the polycomb repressive complex 1and acts as the really interesting new gene finger E3 ligase, which is responsible for histone 2A modification. Previous studies have shown that the ring finger protein 2 (Rnf2) is overexpressed in various types of tumor and has a close association with tumor development. However, few studies have been carried out into the expression and biological function of Rnf2 in gastric cancer cells. The present study measured the expression of Rnf2 in gastric cancer cells and normal epithelial gastric cells. The results demonstrate that Rnf2 is upregulated in gastric cancer cells. In addition, the knockdown of Rnf2 inhibited the cell viability and induced increased G1 phase followed by a substantial reduction of the G2/M phase. The expression levels of p21 and p27 were also significantly elevated by the knockdown of Rnf2. These results provide evidence of the oncogenic function of Rnf2 in gastric cancer, possibly through an inhibition of cellular proliferation and a delay of the G2/M phase. Therefore, Rnf2 may be a novel target for the prognosis and therapy of gastric cancer. IntroductionPolycomb group (PcG) proteins are epigenetic regulators for gene silencing at the transcription level, acting as important regulators of DNA repair, proliferation, embryonic differentiation and cell-fate maintenance during development and in adult tissue homeostasis (1-3). These proteins exist in at least two biochemically and functionally distinct PcG core complexes referred to as polycomb repressive complex (PRC) 1 and 2. PRC2, which is involved in the initiation of gene repression, mediates the trimethylation of histone H3 at Lys27 (H3K27me3) and consists of histone methyltransferase enhancer of zeste homolog 2 (EZH2), the polycomb repressive complex and embryonic ectoderm development (4,5). The mammalian PRC1, which is an ubiquitin E3 ligase complex, consists of polycomb (PC), polyhomeotic (PH), BMI1, ring finger protein (Rnf) 1A and 2 (Rnf2) (6), among which Rnf2 has been identified as the catalytic subunit (7). Rnf2, acts as the RING finger E3 ligase responsible for H2A modification in the PRC1 complex and influences early development and embryonic stem cell maintenance as well as cancer development (8,9). Recent evidence showed that Rnf2 is highly expressed in various types of tumor in comparison to normal tissue counterparts (10). Knockdown of Rnf2 in HeLa cells resulted in morphological changes and an inhibition of cellularproliferation (7), suggesting an oncogenic function of Rnf2. Additionally, it has been reported that Rnf2 can either directly or indirectly target a distinct, specific pathway involved in cell cycle control (11,12). However, in order to acquire a complete understanding of the mechanisms through which cancer progression is regulated by Rnf2, additional investigation is required.Normal cell cycle progression is tightly controlled by a variety of molecular checkpoints, which supervise the biological processes that take place in different...

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Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability

Cited by 51 publications

References 29 publications

The MDM2-p53 pathway revisited

The MDM2-p53 pathway revisited

SHARPIN Facilitates p53 Degradation in Breast Cancer Cells

Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells

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