The Molecular Mechanism Of Ribosomal Protein S26and Apoptosis Associated Protein Bat3in The Regulation Of P53

Cancer, also known as malignant tumors. is a life-threatening disease caused unregulated cell growth which can happen to both human and animals. Inactivation tumor suppressor genes and activation of oncogenes are the main causes for tumorigenesis. The tumor suppressor p53plays a critical role in preventing tumor formation. p53mutations have been found in approximately50%of cancers, and in most of the remaining cancers, the functions of p53are often inhibited. However, in many types of these tumors how p53losses its functions are not well characterized. Therefore finding novel regulators of p53is important in elucidating.Mdm2, as the most important negative regulator of p53, is an E3ubiquitin ligase which can induce p53ubiquitination and degradation to inhibit the functions of p53. In previous study, we found that RPS26can interact with Mdm2and inhibit its E3ubiquitin ligase activity. In this study we further investigated whether RPS26is involved in p53regulation. As a result, we found RPS26has the ability to inhibit Mdm2-mediated p53ubiquitination that leads to p53stabilization upon overexpression. Importantly, we discovered that RPS26knockdown impaired p53’s ability to transcriptionally activate its target genes in response to DNA damage, without affecting its stability. Accordingly, the cells lost the ability to induce G2/M cell cycle arrest. We further found that upon RPS26knockdown, the DNA damage induced p53acetylation and recruitment of p53to the promoters of its target genes were both greatly reduced. In addition, RPS26can interact with p53independent of Mdm2and coexist in a complex with p53and p300. Moreover, knockdown of RPS26induced p53stabilization and activation via a RPL11-dependent mechanism, resulting in p53-dependent cell growth inhibition. These data establish a role of RPS26in DNA damage response by directly influencing p53transcriptional activity.Deubiquitinase HAUSP plays a critical role in p53activation in response to genotoxic and other types of stresses by removing ubiquitin chain from p53. In the previous work, we found Bat3is a potential interacting partner of HAUSP. In this study we confirmed the interaction between Bat3and HAUSP by both endogenous and exogenous co-immunoprecipiation assays. Further we discovered Bat3can regulate the stability of p53though HAUSP. In addition, Bat3enhanced HAUSP’s ability to suppress the Mdm2-mediated p53degradation. These findings suggest that Bat3regulates p53stabilization in a HAUSP-dependent manner.Taken together, we revealed that RPS26, a component of nucleolus. plays a significant role in regulating p53activity upon DNA dainage. In addition, we identified Bat3as a novel HAUSP interacting partner that can modulate the stability of p53through HAUSP. These studies extend the knowledge on the regulation of p53and provide potential targets for cancer therapy.