TITLE:
Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex
AUTHORS:
Pavla Brachova, Samuel R. Mueting, Eric J. Devor, Kimberly K. Leslie
KEYWORDS:
TP53, p53, miRNA, Drosha, Oncomorphic TP53, Gain of Function
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.6,
May
16,
2014
ABSTRACT: Mutations in the tumor
suppressor TP53 occur in
almost all advanced ovarian cancers and in many advanced serous endometrial
cancers. Mutations in TP53
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 harbor TP53
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 oncomorphic TP53 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 specific TP53 mutations: loss of the
enhanced processing of anti-proliferative miRNAs.