title: A common gain of function of p53 cancer mutants in inducing genetic instability.
abstract: The critical tumor suppressor p53 is mutated in over half of all human cancers. The majority of p53 cancer mutations are missense mutations, which can be classified into contact mutations that directly disrupt the DNA-binding of p53 but have modest impact on p53 conformation and structural mutations that greatly disrupt p53 conformation. Many p53 cancer mutants, including the hot spot mutations (R175H, R248W and R273H), not only lose p53-dependent tumor-suppressor activities, but also acquire new oncogenic activities to promote cancer. Therefore, it is critical to elucidate the gain of oncogenic function of p53 cancer mutants. Using humanized p53-mutant knock-in mouse models, we have identified a gain of oncogenic function shared by the most common p53 contact mutants (R273H and R248W) and structural mutant (R175H). This gain of function inactivates Mre11/ATM-dependent DNA damage responses, leading to chromosomal translocation and defective G(2)/M checkpoint. Considering the critical roles of ATM in maintaining genetic stability and therapeutic responses to many cancer treatments, the identification of this common gain of function of p53 cancer mutants will have important implication on the drug resistance of a significant portion of human cancers that express either the contact or structural p53 cancer mutants.
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, La Jolla, CA, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D055879:Gene Knock-In Techniques; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes