title: OncomorphicTP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex.
abstract: Mutations in the tumor suppressorTP53 occur in almost all advanced ovarian cancers and in many advanced serous endometrial cancers. Mutations inTP53 can alter the function of the p53 protein, and some mutations result in a mutated protein with oncogenic activity. Previously referred to as gain of function (GOF) p53 proteins, we now term these "oncomorphic" mutations to better describe their function as oncogenes. We reviewed the data from The Cancer Genome Atlas (TCGA) and demonstrate that of the patients diagnosed with endometrial cancer that harborTP53 mutations, approximately 30% of these mutations are oncomorphic. In ovarian cancer, approximately 20% are oncomorphic. The wild type (WT) p53 protein transactivates genes and micro- RNAs (miRNAs) necessary in the response to cellular stress, which turn off growth and induce apoptosis. In addition to direct transcriptional activation, WT p53 also acts through protein:protein interactions with Drosha and the miRNA processing complex to mediate rapid, enhanced processing of a subset of anti-growth miRNAs. We validated the interaction of WT p53 with the Drosha complex in the cell line UCI-107. We observed that miRNAs that inhibit the expression of oncogenes were induced. Specifically, some miRNAs were induced very rapidly over minutes, consistent with enhanced processing, while others required hours, consistent with transcriptional activation. In contrast, the most common oncomorphicTP53 mutations failed to interact with the Drosha complex and lost the ability to rapidly induce the miRNAs which inhibit oncogene expression. These studies highlight one mechanism underlying the oncomorphic properties of specificTP53 mutations: loss of the enhanced processing of anti-proliferative miRNAs.
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, USA ; Molecular and Cellular Biology Program, University of Iowa, Iowa City, USA.
authors.forename: Pavla
authors.initials: P
authors.lastname: Brachova
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, USA.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Mueting
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Devor
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, USA ; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, USA.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
keywords: Drosha; Gain of Function; Oncomorphic TP53; TP53; miRNA; p53