FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

Park, E., Kim, H., Kim, J. M., Primack, B., Vidal-Cardenas, S., Xu, Y., Price, B. D., Mills, A. A., D’Andrea, A. D. (June 2013) FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis. Molecular Cell, 50 (6). pp. 908-918. ISSN 1097-2765

URL: http://www.ncbi.nlm.nih.gov/pubmed/23806336
DOI: 10.1016/j.molcel.2013.05.017

Abstract

Summary Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > TAp63
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Gene Targeting Service
CSHL labs > Mills lab
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: Matt Covey
Date: 27 June 2013
Date Deposited: 19 Jul 2013 15:20
Last Modified: 02 Feb 2017 16:20
PMCID: PMC3897475
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28446

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving