Timothy H. Carter, Ph.D.

Email: cartert@stjohns.edu

A common theme of my research has been the biochemical and genetic responses of cells to stress, including radiation, chemical carcinogens, and nutrient deprivation. Working primarily in mammalian cells in culture, my students and I discovered a new class of enzyme, the DNA-dependent protein kinase, or DNA-PK1, which we went on to clone and sequence. We determined that it was homologous to PI-3 kinases2, making it the founding member of what become known as the ATM superfamily of protein kinases, which plays a central role in response to radiation and repair of DNA damage. Recently, we have begun working in the area of cancer and nutrition. With colleagues at the North Shore -Long Island Jewish Research Institute, we are investigating why it is people who eat diets rich in cruciferous vegetables (cabbage, Brussels sprouts, cauliflower, kale, and broccoli) get less cervical, breast and prostate cancer. These vegetables contain several anti-cancer compounds, including indole-3-carbinol (I3C), which is converted quantitatively to other compounds in the stomach. One of these, diindolylmethane (DIM), induces apoptosis of cancer cells in vitro and in pre-neoplastic epithelium in vivo3. Furthermore, in both animal models and human clinical trials, a diet supplemented with I3C reduces the incidence and recurrence of both cervical cancer and laryngeal papillomatosis, both diseases with a papillomavirus etiology. We are trying to find out how DIM works, and whether we can make it work even better in a clinical setting. Our results so far suggest that DIM somehow ultimately sensitizes cancer cells to killing by cytokines like TNFa. On the front end, DNA microarray analysis suggests that brief exposure to DIM in vitro invokes the ER-stress response in cancer cells4. We are trying to unravel the signaling pathway(s) altered by DIM, and to tie this in with DIM's ability to prevent cancer without killing normal cells. Our working hypothesis is that the chronic state of nutritional stress experienced by cancer cells within solid tumors may prime the cells to undergo apoptosis when exposed to DIM.

Recent Publications

Carter. T. H., I. Vancurova, I. Sun, W. Lou and S. deLeon (1990). A DNA-Activated Protein Kinase from HeLa Cell Nuclei. Molecular and Cellular Biology 10: 6460-6471.

Poltoratsky, V. P., J.D. York, X. Shi, M. Lieber and T. H. Carter (1995). Human DNA-PK is Homologous to PI Kinases . Journal of Immunology Cutting Edge Papers 15:4529-4533.

Chen, D.-Z., M. Qi,, K. J. Auborn and T. H. Carter (2001) Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplasitic cervical epithelium. Journal of Nutrition 131:3294-3302.

Timothy H.Carter, Kai Liu, Walter Ralph, Jr., DaZhi Chen, Mei Qi, Saijun Fan, Fang Yuan, Eliot M. Rosen and Karen J. Auborn (2002). Diindolylmethane Alters Gene Expression in Human Keratinocytes. J. Nutrition 132:3314-3324

Auborn, K. J., Fan, S., Rosen, E., Goodwin, L., Chandreskaren, A., Williams, D., Chen, D.-Z., and Carter, T.H. Indole-3-Carbinol is a Negative Regulator of Estrogen. J. Nutrition, Nutritional Genomics Supplement, in press (March/April, 2003).

Dr. Carter has been the Director of the Minority Biomedical Research Support program and the Initiative for Minority Student Development, funded by the N.I.H., for the past 9 years, and in addition has received over $3M in research funding from the N.I.H. and the American Cancer Society. His work is currently supported by the N.I.H., the North Shore - Long Inland Jewish Research Institute Foundation, and by private donors.

Graduates of the Carter lab include:

Zahra Zakeri. Ph.D., Prof. of Biological Sciences, City University of New York
Shi-Shin Sun, Ph.D., Asst. Prof. of Otolaryngology, Albert Einstein College of Medicine
Nusrat Malik, Ph.D., Senior Research Scientist, Baylor College of Medicine
Calvin James, Ph.D., Assoc. Prof. of Biochemistry, Ohio University Medical School
Ivana Vancurova, Ph.D., Assistant Professor, Albert Einstein College of Medicine
Vladimir Poltoratsky, Ph.D., Senior Scientist, Columbia University.
Susan deLeon, D.V.M., practicing Veterinarian.