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.

No abstract

The tumor suppressor p53 is mutated in the majority of human cancers, and inactivation of p53 correlates with more aggressive clinical courses and resistance to therapy. Loss of p53 may result in pleiotropic cellular effects such as cell-cycle deregulation, increased survival and aneuploidy. Utilizing the Eµ-myc transgenic mouse as a model system, we previously identified apoptosis as the prime tumor suppressor function of p53 during Myc-driven lymphoma development. However, increasing evidence supports premature senescence as another p53-dependent tumor suppressor program. When exposed to therapy, apoptosis-blocked lymphomas selected against p53, because p53 not only controls apoptosis but also senescence in response to DNA damage. Most of the naturally occurring p53 mutations are missense mutations, preferentially at some ‘hotspots’, which result in expressed mutant proteins. Moreover, different entities show distinct hotspot preferences, implying that individual p53 mutants may have different impact on p53-effector programs, or may even present with novel, oncogenic functions. Revealing the functional impact of mutant p53 on cancer cell biology and subsequent response to treatment is of great interest in the field, and numerous studies including individual mutant knock-in mouse models have been conducted. Nevertheless, no comprehensive approach to elucidate the specific role of the cancer-derived mutations in tumor formation and therapy has been undertaken yet. Our study focuses on the functions of p53 hotspot mutants in a mouse model that faithfully recapitulates human B-cell lymphomagenesis. Mutant p53 constructs were introduced into Eµ-myc transgenic hematopoietic progenitor cells to generate primary malignancies that express individual. Tumor development under different wild-type/mutant p53 combinations was compared and the resulting lymphomas were assayed with particular emphasis on apoptosis and senescence as the key tumor suppressor mechanisms. Most mutants supported rapid tumor development in the presence of wild-type p53, while only some promoted lymphoma formation in p53+/- and p53-null backgrounds. These mutants are selected for since they inhibit p53-dependent apoptosis as the main cause of accelerated lymphoma development. Interestingly, these mutants did not compromise the cellular ability to enter senescence. We found senescence driven by mutant and wild-type p53 not to be strictly dependent on the p53 downstream target p21. The precise mechanism how mutant p53 induces senescence is currently under investigation. Importantly, p53 mutant-specific alterations of pro-apoptotic, pro-senescent and metabolic p53 functions have profound implications for the outcome to cancer therapy in vitro and in vivo, as we will present at the meeting. Our goal is to develop personalized treatment strategies against tumors with defined p53 lesions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2011-240

No abstract