COM4S_M.TTF

Research Focus

The primary area of Dr. Roninson’s research is the mechanisms by which anticancer agents inhibit the proliferation of tumor cells. The first topic of investigation in this area is mitotic catastrophe, a form of cell death that results from abnormal mitosis and that is induced in tumor cells by different classes of chemotherapeutic drugs and radiation. He and his team are characterizing different mechanisms of mitotic catastrophe in tumor cells and the role of cell cycle checkpoints in this process. The other treatment response that they study is terminal growth arrest through the program of cell senescence. They have found that treatment-induced senescence of tumor cells is associated with the induction of multiple genes, which account for different aspects of the senescent phenotype. While some of these genes act as tumor suppressors, a subset of genes induced in senescent cells encode secreted factors with tumor-promoting activities. These activities are mediated in part through the induction of cyclin-dependent kinase inhibitor p21Waf1/Cip1/Sdi1. The team has found that p21 induction leads to transcriptional activation of many genes with potential pathogenic effects. These include secreted tumor-promoting factors, as well as several genes implicated in age-related diseases, such as Alzheimer’s disease, atherosclerosis or arthritis. They are investigating the regulatory mechanisms of senescence-associated changes in gene expression, with a goal of developing drugs that will promote tumor cell senescence or inhibit its undesirable side effects.

The second area of Dr. Roninson’s research is the identification of genes essential for tumor cell growth. This program is based on the methodology for function-based selection of genetic suppressor elements (GSEs). GSEs are short sense- or antisense-oriented gene fragments that inhibit the function of genes from which they are derived. By isolating GSEs that inhibit the growth of tumor cell lines, he and his team have generated a large list of genes that are required for tumor cell proliferation, and they are continuing the identification of such genes in different types of tumor and normal cells. Some of the proteins encoded by these genes are being characterized as tumor-specific targets for the next generation of anticancer drugs.

The research of the Molecular Oncology Laboratory extensively utilizes the deconvolution and confocal microscopy core resources of ORI, in particular for live-cell time-lapse microscopy, as well as the flow cytometric core and Target and Drug Discovery Facility.

Selected Publications

• Chang, B.D., Broude, E.V., Dokmanovic, M., Zhu, H., Ruth, A., Xuan, Y., Kandel, E.S., Lausch, E., Christov, K. and Roninson, I.B. (1999). A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 59: 3761-3767.
• Chang, B.D., Watanabe, K., Broude, E.V., Fang, J., Poole, J.C., Kalinichenko, T.V., and Roninson, I.B. (2000). Effects of p21Waf1/Cip1/Sdi1 on Cellular Gene Expression: Implications for Carcinogenesis, Senescence and Age-Related Diseases. Proc. Natl. Acad. Sci. USA 97: 4291-4296.
• Chang, B.D., Broude, E.V., Fang, J., Kalinichenko, T.V., Abdryashitov, R., Poole, J.C., and Roninson, I.B. (2000). p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19: 2165-2170.
• Chang, B.D., Swift, M.E., Shen, M., Fang, J., Broude, E.V., and Roninson, I.B. (2002). Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic drug. Proc. Natl. Acad. Sci. USA, 99: 389-394.
• Primiano, T., Baig, M., Maliyekkel, A., Chang, B.D., Fellars, S., Sadhu, J., Axenovich, S., Holzmayer, T.A. and Roninson, I.B. (2003). Identification of potential anticancer drug targets through the selection of growth-inhibitory genetic suppressor elements. Cancer Cell, 4: 41-53.

Selected Reviews

• Roninson, I.B., Broude, E.V., and Chang, B.D. (2001). If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resistance Updates 4: 303-313.
• Roninson, I.B. (2002). Oncogenic functions of tumor suppressor p21Waf1/Cip1/Sdi1: association with cell senescence and tumor-promoting activities of stromal fibroblasts. Cancer Lett., 179: 1-14.
• Roninson, I.B. and Gudkov, A.V. (2003). Genetic suppressor element (GSE) methodology and its applications to characterization and identification of tumor suppressor genes. In: Methods in Molecular Medicine: Analysis of Tumor Suppressor Genes, volume I (W.S. El-Deiry, Ed.), Humana Press, pp. 411-434.
• Roninson, I.B. (2003). Tumor cell senescence in cancer treatment. Cancer Res., 11: 2705-2715.