Elsa R. Flores, Ph.D.

The interests of my laboratory are to understand the interplay of the p53 family of genes in anti-tumorigenic processes including DNA damage, apoptosis, tumor suppression, and metastasis. The goal is to use this knowledge to design more targeted therapies for cancer patients with mutations in the p53 pathway.

The complex structure of the p53 family:
Given the structural similarity of p63 and p73 to p53, much excitement erupted over the potential of these genes to be tumor suppressors. Unfortunately, data from human tumors have been difficult to interpret due to the existence of multiple isoforms of p63 and p73 including transactivation competent (TA) isoforms and those lacking the transactivation domain (DN). To understand the mechanisms of these isoforms of p63 and p73 in anti-tumorigenic pathways, my laboratory is taking an in vivo approach by engineering mouse models that are deficient for the TA or DN isoforms.

The p53 family and the DNA damage response:
Using mice deficient for p63 and/or p73, we found that, like p53, they play a pivotal role in the DNA damage pathway. In the absence of p63 and p73, p53 is unable to induce apoptosis in response to DNA damage. The requirement of p63 and p73 is at the level of DNA binding; p53 can bind to target genes involved in cell cycle control but is defective in contacting apoptotic target genes. This data is compelling in that it provides an explanation for a long-standing question in the field of how p53 induces cell cycle arrest in some cellular contexts and apoptosis in others. The mechanism of the cooperation between the p53 family members in the induction of apoptosis in response to DNA damage is currently under investigation in my laboratory. Additionally, we will use cells from our isoform specific knockout mice to determine the contributions of the TA and DN isoforms in this process.

The p53 family members in tumor suppression and metastasis
By aging mice heterozygous for the p53 family members individually or in combination, we found that these mice are highly tumor prone. Tumors from these mice exhibit loss of heterozygosity of the p53 family members and are highly metastatic. Experiments in my lab are designed to understand how the p53 family members suppress tumorigenesis and metastasis.

Recent publications

E.R. Flores. (2007) The roles of p63 in cancer. Cell Cycle 6(3):300–304.
T. Iwakuma, G. Lozano, and E. R. Flores. (2005) Li-Fraumeni Syndrome: a p53 family affair. Cell Cycle 4(7):865–867.
E.R. Flores, S. Sengupta, J.B. Miller, J. Newman, R. Bronson, D. Crowley, A. Yang, F. McKeon, and T. Jacks. (2005) Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 7(4):363–373.
E.E. Reczek, E.R. Flores, A.S. Tsay, L.D. Attardi, and T. Jacks. (2003) Multiple response elements and differential p53 binding control PERP expression during apoptosis. MolCancer Res. 1(14):1048–57.
E.R. Flores, K.Y. Tsai, D. Crowley, S. Sengupta, A. Yang, F. McKeon, and T. Jacks. (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560–4.
de Vries, E.R. Flores, B. Miranda, H.M. Hsieh, C.T. van Oostrom, J. Sage, and T. Jacks. (2002) Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc Natl Acad Sci USA 99(5):2948–53.
M. Irwin, M.C. Marin, A.C. Phillips, R.S. Seelan, D.I. Smith, W. Liu, E.R. Flores, K.Y. Tsai, T. Jacks, K.H. Vousden, and W.G. Kaelin, Jr. (2000) Role for the p53 homologue p73 in E2F1-induced apoptosis. Nature 407: 645–8.