The Promotion Of P53 Acetylation By RLIM Down-regulated In Cervical Cancer Tissues Is Dependent On MDM2, Implication For Cervical Carcinogenesis

RLIM (RING finger LIM domain-binding protein) is identified as a transcriptional co-repressor as well as an E3 ubiquitin ligase to inhibit the transcriptional activities of some LIM-hd (LIM homeodomain) proteins involved in development.Acetylation of tumor suppressor p53 is one of the posttranslational modifications of p53, which is mediated by histone acetyltransferases (HATs). Deacetylation of p53 is the contrary process of acetylation of p53, which is mediated by histone deacetylase (HDACs). MDM2 can inhibit HATs p300/CBP and PCAF mediated p53 acetylation. MDM2 also synergizes HDAC1 to mediate the deacetylation of p53. p53 is a transcription factor with transcriptional activity. Acetylation of p53 is beneficial to p53 transcriptional activation in response to stress.We have found that RLIM can interact with HAT p300 and promotes p300 mediated p53 acetylation. RLIM is a novel protein which can regulate p53 acetylation. The promotion of p53 acetylation by RLIM is dependent on MDM2. RLIM promotes p53 acetylation both through abrogating the inhibitory effect of MDM2 on p300-mediated acetylation of p53 and through inhibiting MDM2-mediated p53 deacetylation.We connet human papillomavirus (HPV) infected cells with the fact that RLIM targets MDM2 to promote p53 acetylation. In HPV positive cervical cancer cell lines the protein level of p53 is low, because viral E6 protein forms complex with human E6-AP protein to mediate ubiquitination and degradation of p53. p53 ubiquitination and degradation is mediated by MDM2 in normal cells. However, in HPV positive cells the ubiquitination and degradation of p53 is mediated by E6/E6-AP complex completely. Since MDM2 is replaced by E6/E6-AP on p53 ubiquitination and degradation in HPV positive cells, the fact that RLIM targets MDM2 to promote p53 acetylation is more important for p53 activation in HPV positive cells than in HPV negative cells. We have found RLIM promotes p53 acetylation in HPV-18 positive cervical cancer derived cell line HeLa cells. And the promotion is dependent on MDM2.95% of cervical cancer is related with HPV infection. However, the presence of HPV is not sufficient for malignant progression of HPV-containing lesions, suggesting that there are still unknown mechanisms existing in the progression from HPV infection to cervical cancer. p53 is mutated in 50% of human tumors while rarely mutated in cervical cancers. In HPV positive cervical cancer cell lines the protein level of p53 is low, because E6/E6-AP complex mediates ubiquitination and degradation of p53. However, p53 is wild type and can be induced to transactivation, leading to cell cycle arrest and apoptosis in these cells. The above suggests that both low protein level of p53 and inhibition of transcriptional activity of p53 may contribute to cervical carcinogenesis.We have found RLIM enhances the transcriptional activity of p53 in HeLa cells and induces apoptosis of the cells. RLIM is downregulated in six out of seven cervical carcinoma tissues we examined. These results indicate that downregulation of RLIM may impair the acetylation of p53 in HPV positive cells, resulting in decreasing of transcriptional activity of p53, leading to cells resistent to apoptosis and to be cancerous. Our work sheds some light in the progression from HPV infection to cervical cancer.