Project 2: Functions of the p53 Family of Genes Arnold Levine, Ph.D. The first goal of this project is to explore the role of p53 in regulating the production of cancer stem cells and induced pluripotent stem cells (iPS). It has been shown that the absence of p53 increases the efficiency of production, reduces the time for production, and eliminates the requirement of two oncogenic transcription factors (myc and KLF-4) as fibroblasts are reprogrammed into IPS cells in culture. We have demonstrated that the loss of wild type p53 functions in cancer cells favors the reprogramming of transcriptional signatures so that cancer cells resemble embryonic stem cells and iPS cells. We are exploring the mechanisms involved in this process of cancer stem cell formation. A set of small molecular weight compounds have been identified that act in the nanomolar range as allele specific synthetic lethal drugs when applied to cells with a p53 codon 175 mutation. These drugs induce apoptosis in codon 175 containing cells, but do not act upon cells with wild type p53, and inhibit cell growth to a lesser extent in cells with other p53 mutant alleles. We are exploring the mechanism of action of this drug. Single nucleotide polymorphisms in the p63 and p73 genes of humans have been identified that act in meiosis of the parents but have phenotypes in the offspring: maternal and paternal effect genes. The phenotypes in the offspring result in higher recombination frequencies, increased copy number variations and aneuploidy. We are employing data bases to determine if such mutations in the offspring can cause cancer at young ages and uncover new tumor suppressor genes.

Public Health Relevance

Maternal and paternal effect genes have been identified that can be passed down to children that possibly may be involved in the development of cancer. We are employing data bases to determine if such mutations in the offspring can cause cancer at young ages and uncover new tumor suppressor genes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
New York
United States
Zip Code
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