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Research Interests:
Defects in the control of cell death lead to a wide variety of diseases, including cancer and degenerative diseases. My research focuses on the molecular mechanisms of programmed cell death (apoptosis) in mammalian cells and its role in cancer therapy and carcinogenesis.
One central question in cancer therapy is how to selectively eliminate cancer cells while preserving normal tissues. Apoptosis evasion is a common feature of cancer and contributes to therapeutic resistance. Restoring apoptosis in cancer cells therefore holds great potentials. We are currently exploring the regulation and role of the BH3-only protein PUMA in the responses to novel anticancer agents such as EGFR inhibitors in head and neck cancer. On the other hand, cancer therapies cause serious damage to normal tissues which limit their clinical effectiveness. Protecting normal tissues during these treatments can therefore be very beneficial to cancer patients. We recently discovered that PUMA-mediated apoptosis is largely responsible for the acute radiation-induced intestinal damage, a major complication of abdominal and pelvic radiotherapy. Blocking PUMA expression protects against radiation-induced injury and improves intestinal stem cell survival and regeneration. The role of PUMA in chemotherapy and radiation-induced mucosal injury and underlying mechanisms will be further determined. Based on the differential regulation of death promoters in cancer and normal cells, targeted and cell-based assays are being developed to identify small molecular modulators of cell death.
Other related research in the laboratory include studies on additional mediators of apoptosis, how a cell makes a decision to enter into different forms of cell death (apoptosis, autophagy and necrosis), and how these mechanisms impact on the therapeutic responses. In addition, mouse tumor models are utilized to understand how apoptosis modulates the initiation, progression and therapeutic responses of cancer.
These above lines of work not only will provide mechanism insights to the regulation of cell death, but also have important clinical ramifications in cancer and diseases associated with aging and tissue injury. Trainees are exposed to most if not all standard techniques in molecular and cell biology, in addition to engineering somatic knock-out and knock-in cells, cell imaging, knockout mouse models and various mouse models in tissue injury and carcinogenesis. Our ongoing collaborations with drug discovery program and physicians will expose trainees to translational cancer research.
Selected Publications:
Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B. PUMA induces the rapid apoptosis in colorectal cancer cells. Mol. Cell 2001 Mar 30;7(3):673-82.
Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc. Natl. Acad. Sci. USA 2003 Mar 100:1931-1936.
Yu J and Zhang, L. No PUMA, no death: implications for p53-dependent apoptosis. Cancer Cell. 2003 Oct;4(4):248-9.
Kohli M*, Yu J*, Seaman C, Bardelli A, Kinzler KW, Vogelstein B, Lengauer C, Zhang, L. SMAC/Diablo-dependent apoptosis induced by non-steroidal anti-inflammatory drugs (NSAIDs) in colon cancer cells. Proc. Natl. Acad. Sci. USA. 2004 Nov 30;101(48):16897-902. *equal contribution
*Yu J, Yue W, Wu B, Zhang L. PUMA Sensitizes Lung Cancer Cells to Chemotherapeutic Agents and Irradiation. Clin Cancer Res. 2006 May 1;12(9):2928-36. *Corresponding author
Wu B, Qiu W, Wang P, Yu H, Cheng T, Zambetti GP, Zhang L, Yu J. p53-independent Induction of PUMA Mediates Intestinal Apoptosis in Response to Ischemia Reperfusion. Gut. 2007 May;56(5):645-54.
Yu J, Wang P, Ming LH, Wood M, Zhang L. SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events. Oncogene. 2007 Jun 21;26(29):4189-98.
Sun Q, Sakaida T, Yue W, Gollin SM, Yu J. Chemosensitization of Head and Neck Cancer Cells by PUMA. Mol Cancer Ther. 2007 Dec;6(12):3180-8.
Qiu W, Carson-Walter EB, Liu H, Epperly M, Greenberger JS, Zambetti, GP, Zhang L, Yu J. PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell. 2008 Jun 5;2(6):576-83.
Ming L, Sakaida T, Yue W, Jha A, Zhang L, and Yu J. Sp1 and p73 activate PUMA following serum starvation. Carcinogenesis. 2008 Oct;29(10):1878-84.
Sun Q, Ming L, Thomas SM, Wang Y, Chen Z, Ferris RL, Grandis JR, Zhang L, Yu J. PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cells. Oncogene. 2009 Jun 18;28(24):2348-57.
Qiu W, Carson-Walter EB, Kuan SF, Zhang L, Yu J. PUMA Suppresses Intestinal Tumorigenesis in Mice. Cancer Res. 2009 Jun 15;69(12):4999-5006
Yu J* and Zhang L* PUMA, A Potent Killer With or Without p53. Oncogene 2009. 28(27): S71-S83. *Corresponding author
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