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Alex Almasan, Ph.D.
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| Area of general research interest:
Genotoxic stress-induced signals for cell cycle control, cell death, and survival. Current program:
Investigators:
Collaborators:
Brief Description: The overall goal of our laboratory is to gain a better understanding of how mammalian cells respond to ionizing radiation (IR) and other therapeutic agents. IR and the therapeutics commonly used in the treatment of cancer are thought to ultimately kill tumor cells by triggering apoptosis. We are interested in the role of the Bcl-2 family and proteolytic caspase substrates, such as Cyclin E, in the regulation of apoptosis. Apoptosis and the cell-cycle arrest induced by IR can occur as a result of the activation of tumor suppressor p53, which transcriptionally induces an inhibitor of the cyclin/CDK complexes. This in turn prevents phosphorylation of the retinoblastoma tumor suppressor protein pRb, thus sequestering the E2F transcription activators, which control expression of S-phase genes. Cyclin E/Cdk2 phosphorylates and thus regulates the function of pRb and related p130 pocket proteins. We are currently extending our previous studies on the role of pRb in apoptosis to that of Cyclin E. Most Cyclin E is proteolytically cleaved in hematopoietic cells. We have identified the site of Cyclin E cleavage and are now addressing the role played by the resulting proteolytic fragment in apoptosis. We are determining subcellular localization and interactions with cellular proteins to address the role of Cyclin E in cell death. The knowledge gained from these studies may lead to a better understanding of the radio- or chemotherapy-induced signals leading to cell death, and ultimately improve cancer therapy by enhancing the elimination of malignant cells. At the same time, this knowledge helps to design strategies for protecting normal cells, tissues, and organs from the harmful effects of radiation. Key References: Chen, Q., Gong, B., and Almasan, A. (2000). Distinct stages of cytochrome c release from mitochondria: a feedback amplification loop linking caspase activation to mitochondria in genotoxic stress induced apoptosis. Cell Death & Diff 7, 227-233. Mazumder, S., Gong, B., and Almasan A. (2000). Activation of cyclin E by genotoxic stress leads to apoptosis of hematopoietic cells. Oncogene 19, 2828-2835. Gong, B. and Almasan, A. (2000). Apo2L/TRAIL and DR5 mediate apoptotic signaling by ionizing radiation in leukemic cells. Cancer Res 60, 5754-5760. Chen, Q., Gong, B, Mahmoud-Ahmed, A., Zhou, A., Hussein, M., and Almasan, A. (2001). Induction of Apo2L and modulation of Bcl-2-related proteins regulate Type I interferon-induced apoptosis in multiple myeloma. Blood 98, 2183-2192. Mazumder, S., Gong, B., Chen, Q., Drazba, J., Buchsbaum, J., and Almasan, A. (2002). Proteolytic cleavage of Cyclin E leads to inactivation of associated kinase activity and amplification of apoptosis in hematopoietic cells. Mol Cell Biol 22, 2398-2409. Chen, Q., Chai, Y., Mazuder, S., Jiang, C, Macklis, R.M., Chisolm, G.M., and Almasan A. (2003). The late increase in free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death & Diff 10, 323-334. Almasan A. and Ashkenazi, A. (2003). Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokines Growth Factor Rev 14, 337-348. Ray, S. and Almasan, A. (2003). Apoptosis induction in prostate cancer cells and xenografts by combined treatment with Apo2L/TRAIL and CPT-11. Cancer Res 63, 4713-4723. DuPree E.L., Mazumder S., and Almasan A. (2004). Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells. Cancer Res 64, 4390-3. Ray, S., Bucur, O., and Almasan, A. (2005). Sensitization of prostate carcinoma cells to Apo2L/TRAIL by a Bcl-2 Family Inhibitor. Apoptosis 10, 1411-1418. Crosby, M.E., Jacobberger, J., Gupta, D., Macklis, R.M., and Almasan, A. (2007). E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma. Oncogene 26,1897-909. Mazumder, S., Plesca, D., Kinter, M., and Almasan A. (2007). Interaction of a Cyclin E fragment with Ku70 regulates Bax-mediated apoptosis in hematopoietic cells. Mol Cell Biol 27, 3511-3520. Ray, S. Shyam, S, Frazier, G., and Almasan A. (2007). S-phase checkpoints regulate Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand and CPT-11-induced apoptosis of prostate cancer cells. Mol Cancer Ther 6, 1368-1378 Plesca, D., Crosby, M.E, Gupta, D., and Almasan, A. (2007). E2F4 Function in G2: Maintaining G2-arrest to Prevent Mitotic Entry with Damaged DNA. Cell Cycle 6, 1147-52. Mazumder, S., Plesca, D., and Almasan A. (2007). A Jekyll and Hyde role of Cyclin E in the genotoxic stress response: Switching from cell cycle control to apoptosis regulation. Cell Cycle. 6, 1437-1442. Rani, M.R., Pandalai, S., Shrock, J., Almasan, A. and Ransohoff, R.M. (2007). Requirement of catalytically-active TYK2 and accessory signals for the induction of TRAIL mRNA by IFN-beta. J Interferon Cytokine Res. 27, 767-779. Mazumder, S., Plesca, D., and Almasan, A. (2007). Caspase-3 activation as a critical determinant of genotoxic stress-induced apoptosis. Methods Mol Biol 414, 13-21. Zhou, Y., Weyman, C., Almasan, A., and Zhou, A. (2008). IFN-gamma induces apoptosis in HL-60 cells through decreased Bcl-2 and increased Bak expression. J Interferon Cytokine Res (in press). Mazumder, S., Plesca, D., and Almasan, A. (2008). DNA damage-induced apoptosis. Methods Enzymol (submitted). Crosby, M.E., Plesca, D,, and Almasan, A(2008). Role of E2F4 in the therapeutic response. In: “Control of cellular physiology by transcription factors E2F”. Ed: Yashida, K. Research SignPost (in press). Gupta D., Arora, R., Almasan, A., Gudkov, A.V, and Macklis, R.M. (2008). Modification of the biological effects of Low LET radiation on mitochondria. In: "Herbal Radiomodulators: Applications in Medicine, Homeland Defense and Space", CAB International, UK (submitted). Gupta, D., Crosby, M.E, Almasan, A., and Macklis, R.M. (2008). Regulation of CD20 expression by radiation-induced changes in intracellular redox milieu. Free Radicals in Biol Med (accepted). | ||
