Project 4: Roles and Regulation of Mutant p53 and p63 Isoforms in Urothelial Development and Bladder Cancer Progression Carlos Cordon-Cardo, M.D., Ph.D. Cumulative observations by our group led us to hypothesize that the molecular processes by which p53 and p63 regulate urothelial differentiation are causally linked to their role in bladder tumor initiation and progression. Our main objective is to define the critical functions of p53 and p63-isoforms in urothelial development, bladder cancer initiation and progression. For this purpose, we will use state-ofthe- art molecular pathology and genetic approaches utilizing in vitro cell-based assays and in vivo mouse models, validating significant findings in human normal and tumor bladder tissues.
The specific aims are:
Aim #1. Comprehensive analysis of p53 and p63-isoforms during urothelial development. We discovered that p63 is essential for urothelial differentiation, and that p63-null mice developed an abnormal mono-cellular layer urothelium. Prelimianry data supports that this layer is constituted of

Public Health Relevance

Understanding critical processes regulated by p53 family members implicated in urothelial development and bladder tumor initiation will enhance our search for urothelial stem cells and related bladder cancer stem cells. Our studies have significant translational implications through the definition of a novel urothelial histogenesis model based on p63-differentiation pathways, determining and validating the predictive nature of p53 and p63 alterations in bladder cancer, and identifying candidate bladder cancer stem cells. In sum, results from these studies will have far reaching implications regarding bladder cancer prognosis and establishing effective treatment, thus assisting in the implementation of

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA087497-13
Application #
8566830
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
13
Fiscal Year
2013
Total Cost
$421,579
Indirect Cost
$79,622
Name
Columbia University (N.Y.)
Department
Type
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Miething, Cornelius; Scuoppo, Claudio; Bosbach, Benedikt et al. (2014) PTEN action in leukaemia dictated by the tissue microenvironment. Nature 510:402-6
Jia, A Y; Castillo-Martin, M; Bonal, D M et al. (2014) MicroRNA-126 inhibits invasion in bladder cancer via regulation of ADAM9. Br J Cancer 110:2945-54
Barber, Alison G; Castillo-Martin, Mireia; Bonal, Dennis M et al. (2014) Characterization of desmoglein expression in the normal prostatic gland. Desmoglein 2 is an independent prognostic factor for aggressive prostate cancer. PLoS One 9:e98786
Chen, Chong; Liu, Yu; Rappaport, Amy R et al. (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25:652-65
Jia, Angela Y; Castillo-Martin, Mireia; Domingo-Domenech, Josep et al. (2013) A common MicroRNA signature consisting of miR-133a, miR-139-3p, and miR-142-3p clusters bladder carcinoma in situ with normal umbrella cells. Am J Pathol 182:1171-9
Mills, John R; Malina, Abba; Lee, Teresa et al. (2013) RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an E?-myc/Bcl-2 mouse model. Blood 121:3402-12
Freed-Pastor, William A; Mizuno, Hideaki; Zhao, Xi et al. (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148:244-58
Shen, Tian Huai; Gladoun, Nataliya; Castillo-Martin, Mireia et al. (2012) A BAC-based transgenic mouse specifically expresses an inducible Cre in the urothelium. PLoS One 7:e35243
Karni-Schmidt, Orit; Castillo-Martin, Mireia; Shen, Tian Huai et al. (2011) Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression. Am J Pathol 178:1350-60
Wosnitzer, Matthew S; Domingo-Domenech, Josep; Castillo-Martin, Mireia et al. (2011) Predictive value of microtubule associated proteins tau and stathmin in patients with nonmuscle invasive bladder cancer receiving adjuvant intravesical taxane therapy. J Urol 186:2094-100

Showing the most recent 10 out of 68 publications