Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex

Pavla Brachova; Samuel R. Mueting; Eric J. Devor; Kimberly K. Leslie

doi:10.4236/jct.2014.56058

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Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex

Journal article

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Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex

Pavla Brachova, Samuel R. Mueting, Eric J. Devor and Kimberly K. Leslie

Journal of cancer therapy, Vol.5(6), pp.506-516

05/16/2014

DOI: 10.4236/jct.2014.56058

PMCID: PMC4203685

PMID: 25339994

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Abstract

Mutations in the tumor suppressor TP 53 occur in almost all advanced ovarian cancers and in many advanced serous endometrial cancers. Mutations in TP 53 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 TP 53 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 TP 53 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 TP 53 mutations: loss of the enhanced processing of anti-proliferative miRNAs.

Drosha

Gain of Function

miRNA

Oncomorphic TP53

p53

TP53

Details

Title: Subtitle: Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex
Creators: Pavla Brachova - University of Iowa
Samuel R. Mueting - University of Iowa
Eric J. Devor - University of Iowa
Kimberly K. Leslie - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, USA ; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, USA.
Resource Type: Journal article
Publication Details: Journal of cancer therapy, Vol.5(6), pp.506-516
DOI: 10.4236/jct.2014.56058
PMID: 25339994
PMCID: PMC4203685
NLM abbreviation: J Cancer Ther
ISSN: 2151-1934
eISSN: 2151-1942
Language: English
Date published: 05/16/2014
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9984317111802771

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