University of Medicine and Dentistry of New Jersey

Cohen, T.J., Mallory, M.J., Strich, R., and Yao, T.P. The Hos2p/Set3p deacetylase complex signals secretory stress through the Mplk1p cell-integrity pathway. Eukaryotic cell. E. PUB.. Vol. : (2008 ) .

Michael J. Mallory, Katrina F. Cooper, and Randy Strich Meiosis-specific destruction of the Ume6p transcriptional repressor by the Cdc20-directed APC/C. Molecular Cell. Vol. 27: 951-961 (2007 September ) .

Krasely, E., K. F. Cooper, M. J. Mallory, R. L. Dunbrack, Jr., and R. Strich. Regulation of the Oxidative Stress Response Through Slt2p-Dependent Destruction of Cyclin C in S. cerevisiae. Genetics . Vol. 172: 1477-1486 (2005 ) .

Strich, R. M. Mallory, M. Jarnik, K.F. Cooper. Cyclin B-Cdk activity stimulates meiotic re-replication in budding yeast. Genetics. Vol. 167: 1621-1628 (2004 ) .

Dimitrova, I., G. G. Toby, E. Tilid, R. Strich, S. C. Kampranis, and A. M. Makris. Expression of Bax in yeast affects not only the mitochondria but also vacuolar integrity and intracellular protein traffic.. FEBS Lett . Vol. 566: 100-104 (2004 ) .

Cohen, T., K. Lee L. Rutkowski and R. Strich Ask10p mediates the oxidative stress-induced destruction of the yeast C-type cyclin Ume3p/Srb11p. . Euk. Cell.. Vol. 2: 962-970 (2003 ) .

Mallory, M. J. and R. Strich Ume1p represses meiotic gene transcription in S. cerevisiae through interaction with the histone deacetylase Rpd3p.. J. Biol. Chem.. Vol. 278: 44727-44734 (2003 ) .

Cooper, K.F. and R. Strich. The yeast C-type cyclin Ume3p/Srb11p is required for the efficient induction and execution of meiotic development in S. cerevisiae. . Euk. Cell. . Vol. 1: 67-77 (2002 ) .

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Grants and Contracts

Title: Role of Oxidative Stress in Drug Resistance (CA099003)
Sponsor: National Institutes of Health-NCI
Effective Date(s): 2003 - 2008
Role: P.I.

Title: Training Program in Cancer Research (T32CA009035)
Sponsor: National Institutes of Health-NCI
Effective Date(s): 2001 - 2005
Role: P.I.

Title: Cyclin C-Cdk8 Function as a Tumor Suppressor
Sponsor: Tobacco Formula Grant-PA
Effective Date(s): 2005 - 2005
Role: P.I.

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Research Areas

Regulation of meiotic gene development and the stress response in yeast: Our research focuses on two main questions. First, resistance to anti-cancer agents is the predominant reason why chemotherapy regimens fail to eradicate disseminated malignancies. Therefore, elucidating the resistance mechanisms is of great importance for improving patient outcome. The pathway that responds to reactive oxygen species (ROS) appears to be of singular importance for influencing drug sensitivity. My laboratory identified the conserved yeast cyclin C-cyclin dependent kinase 8 as important regulators of the ROS response and programmed cell death in budding yeast. We are currently expanding these studies into the mouse system to determine how this pathway influences drug sensitivity in both normal and transformed cells. Second, meiosis is a specialized, highly conserved process designed to redistribute the genetic material and produce haploid cells capable of sexual reproduction. Unlike mitotic cell division, little is known about how the different meiotic landmark events are coordinated. My laboratory investigates the regulation of genes required for meiotic development in the budding yeast S. cerevisiae. Specifically, we are studying the interplay between transcription factor regulation and chromatin remodeling that mediates the transient transcription expression profiles observed during meiosis. Research Grants: NIH RO1 "Role of the Oxidative Stress Pathway in Drug Resistance." Cellular resistance to anti-cancer agents is the predominant reason why chemotherapy regimens fail to eradicate disseminated malignancies. Therefore, elucidating the resistance mechanisms is of great importance for improving patient outcome. Several mechanisms for drug resistance have been identified including elevated drug pump activity and p53 mutation. In addition, the drug sensitivity of many tumors is influenced by induction of the stress response pathway. Moreover, the pathway that responds to reactive oxygen species (ROS) appears to be of singular importance for influencing drug sensitivity. However, the molecular mechanisms underlying the role of the ROS pathway in altering the drug response are largely unknown. The long term goal of this proposal is to fully describe the ROS response system and determine how this pathway influences drug sensitivity in both normal and transformed cells. Over the last few years, my laboratory has made two important contributions to understanding how the ROS damage signal is transduced to the nucleus to remodel the transcription program in the budding yeast S. cerevisiae. First, we found that the C-type cyclin-cyclin dependent kinase Ume3p-Ume5p represses the transcription of several genes involved in the stress response. To relieve this repression, Ume3p is destroyed in cells exposed to several stressors including reactive oxygen. Moreover, we demonstrated that the human cyclin C (HcycC) is also down regulated in both yeast and mammalian cells subjected to stress indicating that this system is remarkably well conserved. These findings established a second paradigm for the regulated destruction of a cyclin molecule that is independent of cell cycle progression. Second, we found that the oxidative stress signal that triggers Ume3p destruction is transduced by the important signaling protein phosphatidylinositol-specific phospholipase C (PLC1). Plc1p is most closely related to Plcg in humans which has also been shown to be activated by ROS exposure. Therefore, the ROS response pathway appears to be well conserved between yeast and man. Moreover, these results provide two initial targets to study the impact of the ROS pathway on the drug response in tumor cells.

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