James DiRenzo, Ph.D.
Assistant Professor of Pharmacology and Toxicology
Scientific Co-Director of the Breast Clinical Oncology Program
| Contact Information |
| Phone: 603-650-1794 |
| Fax: 603-650-1129 |
| Labphone: |
| Email Address: james.direnzo@dartmouth.edu |
| Website: http://cobweb.dartmouth.edu/cgi-bin/cgiwrap/~dms/facultydb/profile_read.pl?uid=146 |
| Laboratory Website : http://www.dartmouth.edu/dms/pharmtox/ |
Postal Address |
| Dr. James DiRenzo |
| 7650 Remsen |
| Dept. of Pharmacology and Toxicology, DMS |
| Hanover NH 03755 |
Education |
| University of California, San Diego School of Medicine, Ph.D. 1995 |
Program Membership |
| Cancer Mechanisms Research Program |
Department Membership |
| Pharmacology & Toxicology |
Graduate Training Program Affiliation |
| Pharmaclogy and Toxicology |
Biography |
| Dr. DiRenzo received his Ph.D. from the University of California, San Diego School of Medicine in 1995. He received post-doctoral training from 1995 through 1999 in the Department of Adult Oncology at the Dana Farber Cancer Institute at Harvard. Since 1999, he has continued his studies at the Dana Farber as an Instructor in Medicine. Dr. DiRenzo joined the Department of Pharmacology and Toxicology at Dartmouth as an Assistant Professor in the summer of 2001 |
| Our laboratory is interested in the genetic control of cellular differentiation within the mammary gland. The epithelial portion of the mammary gland is a dynamic structure that undergoes successive regenerative cycles of proliferation, acquisition of physiologic function and cell death. The death of mature terminally differentiated cells is balanced by activities of basal progenitors, which must survive developmentally regulated cell death and re-initiate proliferation during re-population of the gland. During this proliferative phase, basal progenitors execute a critical decision to either retain their proliferative capacity and de-differentiated phenotype (self-renewal) or initiate a program of cellular differentiation (commitment). A critical determinant of this decision is the expression status of a member of the p53 family of transcriptional regulators called DN-p63. DN-p63 directly opposes many of the activities of p53 by acting as a dominant negative regulator of p53-target genes. Several studies have shown that the expression of DN-p63 is required for maintenance of self-renewal within the basal progenitor lineage. Other studies have shown that repression of DN-p63 expression is required for commitment. |
| The major goals of our laboratory are: 1. To understand the mechanisms underlying the decision to self-renew or commit to differentiation by identifying factors which regulate transcriptional activity of the gene encoding DN-p63. Recent studies from out lab demonstrate that DN-p63 is a direct transcriptional of p53. This suggests that p53 may play a role in self-renewal by directing expression of a factor that opposes its downstream activities. 2. To understand the role of DN-p63 in the preservation of basal progenitors during developmentally regulated apoptosis. 3. To identify downstream effectors of DN-p63 that are expressed as a result of disruption of DN-p63 expression or activity, and to determine the contributions of these genes to cellular differentiation. |
Selected Recent PublicationsHarmes, D.C., Bresnick, E., Lubin, E.A., Watson, J.K., Heim, K.E., Curtin, J.C., Suskind, A.M., Lamb, J., and DiRenzo, J. (2003). Positive and negative regulation of deltaN-p63 promoter activity by p53 and deltaN-p63-alpha contributes to differential regulation of p53 target genes. Oncogene 22, 7607-7616. Kerley-Hamilton, J.S., Pike, A.M., Li, N., DiRenzo, J., and Spinella, M.J. (2005). A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. Oncogene 24, 6090-6100. Li, N., Li, H., Cherukuri, P., Farzan, S., Harmes, D.C., and DiRenzo, J. (2006). TA-p63-gamma regulates expression of DeltaN-p63 in a manner that is sensitive to p53. Oncogene 25, 2349-2359. Nakuci, E., Mahner, S., DiRenzo, J., and Elshamy, W.M. (2006). BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells. Exp Cell Res. 312, 3120-31. Li, H., Cherukuri, P., Li, N., Cowling, V., Spinella, M., Cole, M., Godwin, A.K., Wells, W., and DiRenzo, J. (2007). Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res 67, 501-510. |
Research / Lab InterestsDr. DiRenzo's research focuses on genetic pathways underlying self-renewal in mammary stem cells and their contributions to breast cancer initiation and progression. Project 1 aims to understand the mechanisms by which TP63, a p53 family member required for preservation of self-renewal, regulates preservation and forfeiture of self-renewal. Gain-of-function and loss-of-function studies indicate that DN-p63-a, the most common isoform of TP63 mediates a mitogen-induced program of self-limitation in which cells expressing DN-p63-a become quiescent following completion of the cell cycle. These studies indicate that this program is active in primary mammary stem cells isolated from mice, immortalized mammary epithelial cells and breast cancer cell lines. We hypothesize that this mechanism confers upon mammary stem cells a prolonged life-span by limiting cell division and telomeric erosion. Project 2 aims to elucidate the role of hedgehog signaling in the mammary regenerative cycle. Our studies have identified reciprocal interactions between hedgehog signaling and TP63 that mediate the elaboration of mammary progenitors by mammary stem cells. In collaboration with the NCCC Flow-cytometry Shared Resource, isolation and analysis of primary mammary stem and progenitor cells identified a developmental signal that stimulates asymmetric mitosis by mammary stem cells resulting in the preservation of the stem cell pool and the expansion of the progenitor pool. These studies coupled to evidence of hedgehog hyperactivation in breast cancer suggest that hedgehog-mediated stimulation of breast cancer stem cells may promote breast cancer initiation. Project 3 aims to test the hypothesis that breast tumor aggressiveness correlates with stem cell content within a tumor. To address this hypothesis, in collaboration with Michael Cole, we have developed a strategy that has resulted in the identification and validation of >30 stem cell-specific or stem-cell-selective molecular markers. Analysis of expression of these markers in breast tumors has indicated that nestin is a selective marker of the basal-epithelial breast cancer subtype (as defined by Perou et al) and is therefore predictive of tumor aggression, age of onset, short-time to relapse and overall poor prognosis. Selection and analysis of breast tumors representing all five molecular subtypes of breast cancer was done in collaboration with Wendy Wells and the NCCC Research Pathology Shared Resource. Project 4 aims to develop transgenic targeting strategies that will selectively target mammary stem cells. The currently developed strategy uses the DN-p63-promoter to achieve epithelial stem cell specificity and a mammary-specific Cre-recombinase to achieve mammary gland specificity. Analysis of first generation mice indicates that the DN-p63-promoter is selectively active in Lin-/CD24+/CD29High mammary epithelia indicating exclusive expression in a mammary stem cell enriched fraction. The goal of these studies is to target diverse oncogenes selectively into mammary stem cells to determine if the nature of the oncogenic lesion determines the breast cancer subtype. This project has benefited greatly from the skill of the NCCC Flow Cytometry Shared Resource. Project 5 aims to elucidate the contributions of Notch signaling in TP63-mediated cell fates. Our studies have identified genetic interactions between TP63 and Notch1 and the notch regulator, Numb. Analysis of these interactions indicates that loss of DN-p63-a leads to the stabilization of numb during the elaboration of mammary progenitors by mammary stem cells. Our goal is to elucidate the mechanisms by which this occurs and to determine if these mechanisms contribute to notch-mediated breast cancer initiation. |
Grants, Honors, Invited Lectures |
| General Motors Cancer Research Foundation Scholars Award. (January 2002-January 2004). |
| The V Foundation For Cancer Research Scholars Award. (August 2003-August 2005). |
