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.