MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity

The tumor suppressor p53 is extensively regulated by post-translational modification, including modification by the small ubiquitin-related modifier SUMO. We show here that MDM2, previously shown to promote ubiquitin, Nedd8 and SUMO-1 modification of p53, can also enhance conjugation of endogenous SUMO-2/3 to p53. SUMOylation activity requires p53-MDM2 binding but does not depend on an intact RING finger. Both ARF and L11 can promote SUMO-2/3 conjugation of p53. However, unlike the previously described SUMO-1 conjugation of p53 by an MDM2-ARF complex, this activity does not depend on the ability of MDM2 to relocalize to the nucleolus. Interestingly, the SUMO consensus is not conserved in mouse p53, which is therefore not modified by SUMO-2/3. Finally, we show that conjugation of SUMO-2/3 to p53 correlates with a reduction of both activation and repression of a subset of p53 target gene

Functional interplay between MDM2, p63/p73 and mutant p53

Many cancers express mutant p53 proteins that have lost wild-type tumor suppressor activity and, in many cases, have acquired oncogenic functions that can contribute to tumor progression. These activities of mutant p53 reflect interactions with several other proteins, including the p53 family members p63 and p73. Mutations in p53 that affect protein conformation (such as R175H) show strong binding to p63 and p73, whereas p53 mutants that only mildly affect the conformation (such as R273H) bind less well. A previously described aggregation domain of mutant p53 is not required for p63 or p73 binding; indeed, mutations within this region lead to the acquisition of a mutant p53 phenotype—including a conformational shift, p63/p73 binding and the ability to promote invasion. The activity of wild-type p53 is regulated by an interaction with MDM2 and we have investigated the potential role of MDM2 in the mutant p53/p63/p73 interactions. Both mutant p53 and p73 bind MDM2 well, whereas p63 binds much more weakly. We found that MDM2 can inhibit p63 binding to p53R175H but enhances the weaker p53R273H/p73 interaction. These effects on the interactions are reflected in an ability of MDM2 to relieve the inhibition of p63 by p53R175H, but enhance the inhibition of p73 activity by p53R175H and R273H. We propose a model in which MDM2 competes with p63 for binding to p53R175H to restore p63 activity, but forms a trimeric complex with p73 and p53R273H to more strongly inhibit p73 function

Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC

BACKGROUNDS:p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options. METHODS:In this study, we used immunoprecipitation, immunofluorescence, clonogenic survival, and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells. RESULTS:Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo. CONCLUSIONS:The data presented here suggest a therapeutic potential of targeting mutant p53 protein in advanced PCa setting, which has a clinical impact for aggressive PCa with transforming how such tumors are managed

Ginkgo biloba, DNA damage and DNA repair: overview

Despite the ancient use in Chinese popular medicine and, more recently, in western modern medicine in many European countries, the biological effects of extracts of G. biloba (GBE) are still not clearly known. In modern medicine GBE has been used for tinnitus, to reverse memory loss, for dementia, and Alzheimer's and Parkinson's diseases in elderly people. Besides reports on improvement of blood circulation in the brain, there are a number of studies pointing to complex cellular effects, involving signal transduction pathways and epigenetic modifications. Evidence are presented from recent reports concerning genotoxic and antigenotoxic properties and the corresponding mechanisms underlying such activities, mostly regarding the prooxidant and antioxidant activities of the extract. However, several examples of direct interaction of the extract and its components with specific proteins are provided, especially for DNA damage repair, contributing for antigenotoxicity. Evidence of epigenetic effects of GBE are also presented from approaches involving transcriptomics, detection of activity of histone deacetylases, and screening of plant extracts with cell-based systems for detection of posttranslational modifications. The modulation of chromatin-remodeling enzymes by GBE and their interaction with proteins involved in DNA damage repair, apoptosis, and signal transduction are discussed in the context of neurodegeneration.(undefined)info:eu-repo/semantics/publishedVersio