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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:
- DNA damage responses: radiation-regulated genes (focus on hematologic and epithelial tumors).
- Integration of cellular radiation responses: cell death and cell cycle control.
- Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.
Investigators:
- Sayer Rashed Al-Harbi, Graduate Student
- Suparna Mazumder, Ph.D., Project Scientist
- Arishya Sharma, Graduate Student
- Kamini Singh, Ph.D., Research Fellow
Collaborators:
- Andrei Gudkov, Ph.D., Roswell Park Cancer Institute, Buffalo, NY
- Jaroslav Maciejewski, M.D., Ph.D, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
- Shigemi Matsuyama, Ph.D., Department of Medicine-Hematology/Oncology, CASE Western Reserve University, Cleveland, OH.
- Matt Kalaycio, M.D., Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
Brief Description:
We investigate the molecular basis of cell death and cell cycle control regulation and how these processes are coordinated during genotoxic stress responses, particularly following exposure to ionizing radiation.
Our laboratory’s efforts are directed to three major projects. In the first, we seek to understand DNA damage signals incurred by mammalian cells following ionizing radiation. We study ionizing radiation-regulated genes, with a focus on those that play an important role in cell-cycle checkpoints, cell proliferation and death in hematologic and epithelial tumor cells.
The second project is focused on understanding how the two fundamental cellular responses to irradiation – cell death (apoptosis, autophagy) and cell cycle control – are integrated. Our recent studies have shown that cyclin E undergoes a proteolytic, caspase-mediated cleavage during the early stages of apoptosis in hematopoietic cells. The resulting C-terminal fragment of cyclin E can no longer sustain cell-cycle regulation as it cannot bind to its catalytic partner Cdk2; instead, it binds to the DNA repair protein Ku70. As a result (i) in the nucleus it impairs DNA repair by preventing recruitment of accessory proteins (DNA ligase IV, XRCC4, and XLF) to the DNA repair complex assembled on double-stranded DNA, and (ii) in the cytoplasm, it dislocates BAX from KU70, triggering BAX activation and its translocation to mitochondria.
The third project focuses on a tumor-specific cell death ligand, Apo2L/TRAIL, its role in cell death signaling and biology, and its potential for cancer therapy in epithelial and hematologic malignancies.
Key References:
Chen, Q., Gong, B., 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., Almasan A. (2000). Activation of cyclin E by genotoxic stress leads to apoptosis of hematopoietic cells. Oncogene 19, 2828-2835.
Gong, B. 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., 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., 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., 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., Ashkenazi, A. (2003). Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokines Growth Factor Rev 14, 337-348.
Ray, S., 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., 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., 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., 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., 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., 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., 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., 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., 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., Almasan, A. (2008). Caspase-3 activation as a critical determinant of genotoxic stress-induced apoptosis. Methods Mol Biol 414, 13-21.
Zhou, Y., Weyman, C., Almasan, A., Zhou, A. (2008). IFN-gamma induces apoptosis in HL-60 cells through decreased Bcl-2 and increased Bak expression. J Interferon Cytokine Res 28:65-72.
Mazumder, S., Plesca, D., Almasan, A. (2008). DNA damage-induced apoptosis. Methods Enzymol 446:107-122.
Crosby, M.E., Plesca, D, Almasan, A(2008). Role of E2F4 in the therapeutic response. In: “Control of cellular physiology by transcription factors E2F”. Ed: Yashida, K. Research SignPost, Chapter 23, 401-412.
Gupta, D., Crosby, M.E, Almasan, A., Macklis, R.M. (2008). Regulation of CD20 expression by radiation-induced changes in intracellular redox milieu. Free Radicals in Biol Med 44:614-623.
Plesca D., Mazumder S., Gama V., Matsuyama S., Almasan A. (2008). A C-terminal fragment of Cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron. J Biol Chem 283:30796-30803.
Gupta D., Arora R., Mohan RR., Almasan A., Gudkov AV., Macklis RM. (2008). Novel strategies for protecting mitochondria (the cellular powerhouse) against Low LET radiation. In: "Herbal Radiomodulators: Applications in Medicine, Homeland Defense, and Space," Chapter 15, 215-226. CAB International, UK.
Singh K., Eisermann K., Piontkivska H., Frazier G., Almasan A. (2009). Common signaling pathways in prostate cancer: importance of coordinate gene regulation. In: "Prostate Cancer Cells: Growth, Signaling, and Survival," Ed: Columbus F., NOVA Publishers, Hauppauge, NY.