Assistant Professor

•  B.S. Chemistry, California State University, Long Beach, 1977
•  Ph.D. Biochemistry, University of California, Riverside, 1986

Research Interests

•  Initiation of DNA replication and cell cycle regulation in human cells
•  Modulation of TNF-mediated tumor cell cytotoxicity
•  Molecular mechanisms of soft tissue tumorigenesis

Current Research

Initiation of DNA replication

The initiation of DNA replication in mam­malian cells is a series of highly regulated, spatially and temporally coordinated events, and we are interested in how defects in this process may relate to transformation and carcino­genesis. We have focused on a 7 kb DNA sequence from the highly amplified human ribosomal RNA gene which contains a chromosomal replication origin, and have identified several preferred replication initiation sites within this region. We have also found that replication initiates at different sites as S phase progresses, with replication in early S phase beginning several thousand base pairs distant from the preferred sites of replication initiation in late S phase. We are currently examining protein binding to this region in vivo and in vitro , and are interested in defining protein interactions that facilitate origin function at active initiation sites, and that repress origin function at potential initiation sites that are not utilized. As vectors containing the 7 kb rDNA sequence are capable of episomal replication following transfection into 293 cells, deletion and site-specific mutagenesis experiments are in progress to determine the minimum sequences necessary for origin function in these systems.

TNF Cytotoxicity

The clinical utility of the cytokine tumor necrosis factor (TNF) as an antitumor agent has been greatly limited by it's systemic effects, notably the induction of septic shock. Previous studies have shown that certain inhibitors of DNA topoisomerase II, that are currently in clinical use as antitumor agents, can dramatically enhance the cytotoxic activity of TNF towards tumor cells, raising the possibility that tumor cells may be sensitized to the cytotoxic effects of TNF at concentrations below those required to induce harmful systemic effects. We are currently focusing on the interactions of two DNA topoisomerase II inhibitors, the epipodophyllotoxins VP-16 and VM-26, with TNF and TNF-initiated signal transduction pathways, particularly their effects on the NF-kB and JNK activation.

Soft Tissue Tumorigenesis

A more recent research interest centers on changes in gene expression that accompany the development of high grade soft tissue sarcomas. Soft tissue sarcomas represent a small percentage of tumors diagnosed on a yearly basis in the United States, but prognosis is poor for high grade tumors and a significant percentage of cases result in patient mortality. Identification of genes that are significantly up or down regulated during high grade tumor development would provide useful diagnostic and prognostic markers, and possibly define proteins or pathways amenable to therapeutic intervention. Array analysis of graded tumor specimens has identified a handful of genes that appear consistently upregulated or downregulated in high grade soft tissue sarcomas. Of particular interest are the chitinase gene family, several of which have been found to be upregulated in patients with other types of cancer (breast, colon, glioma) as well as some chronic inflammatory conditions.

Representative Publications:

Baloch, Z., Cohen, S., Fresa, K., and Coffman, F.D. Modulation of topoisomerase activities by tumor necrosis factor. Cell. Immunol., 160:98-103, 1995.

Coffman, F.D., and Cohen, S. Regulation of DNA replication initiation in mammalian lymphocyte systems. Indian J. Biochem. Biophys., 34:192-198, 1997.

Coffman, F.D., and Cohen, S. Regulation of DNA replication initiation in mammalian lymphocyte systems. Indian J. Biochem. Biophys., 34:192-198, 1997.

Wang, Q., Luo, X., Kheir, A., Coffman, F.D., and Studzinski, G.P. Retinoblastoma protein-overexpressing HL60 cells resistant to 1,25-dihydroxyvitamin D3 display increased CDK2 and CDK6 activity and shortened G1 phase. Oncogene, 16:2729-2737, 1998.

Coffman, F.D. and Studzinski, G.S. Differentiation-related mechanisms which suppress DNA replication. Exp. Cell Res,. 248 : 58-73, 1999.

Wang, Q., Studzinski, G.P., Chen, F., Coffman, F.D. and Harrison, L. E. p53/56lyn antisense shifts the 1,25 dihydroxyvitamin D3-induced G1/S Block in HL60 cells to S phase. J. Cell. Physiol., 183: 238-246, 2000.

Chong S. Y., Lin, Y-C., Czarneski, J., Zhang, M., Coffman, F., Kashanchi, F., and Raveche E. Cell cycle effects of IL-10 on malignant B-1 cells. Genes & Immunity, 2(5):239-47, 2001.

Coffman, F.D., He, M., Diaz, M.-L, and Cohen, S. Preferred initiation sites within the human rDNA replication origin. (Submitted).

Coffman, F.D., He, M., Diaz, M.-L. and Cohen, S. DNA replication initiates at different sites in early and late S phase within human ribosomal RNA genes. (Submitted)