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RESEARCH EXPERTISE:
Apoptosis (programmed cell death) is a physiological process used by higher eukaryotes to selectively remove cells that are no longer needed, damaged or dangerous. Deregulated apoptosis contributes to a wide variety of diseases. My research focuses on the molecular mechanisms of apoptosis regulation in cancer biology and therapy.
There are three major ongoing research areas in the lab: 1) cell death mechanisms in cancer cells, 2) intestinal stem cells in injury and carcinogenesis, and 3) apoptosis-targeted drug development. Our major focus is the regulation of BH3-only protein such as PUMA in apoptosis induced by cancer therapies targeting survival pathways and oncogenic kinases. We recently started to explore molecular switches controlling distinct apoptotic pathways, and apoptosis with other forms of cell death, i.e., autophagy, necrosis and mitotic catastrophe via mitochondria and bioenergetics. Using mouse models coupled with stem cell lineage marking and tracing, we are probing the role of apoptosis and stress response in intestinal damage, regeneration and carcinogenesis, currently focusing on the p53/PUMA/p21 and IAP/SMAC/NF- B pathways. Lastingly, we are engaged in developing small molecules as potential apoptosis-targeted therapies using cell-based assays as well as computational biology-assisted approaches. The long term goal of our research is to understand the complex role of apoptosis and its regulation, and identify novel targets in cell death pathways for cancer treatment and normal stem cell protection.
A wide variety of approaches are employed in our studies, including molecular and cell biology techniques, engineering somatic knockout and knockin cancer cell lines, state-of-art cell imaging, transgenic and knockout mouse models, injury and cancer models, and correlative studies using clinical samples.
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. (Featured in Nature Reviews of Molecular Cell Biology 2:319, 2001)
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*, 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.
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. (Previewed in Cell Stem Cell 2: 517-518, 2008 and highlighted in Nature Biotechnology 26 (7): 777, 2008).
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.
Yu J* and Zhang L PUMA, A Potent Killer With or Without p53. Oncogene 2008 Dec Suppl 1: S71-S83. Review. * Co-corresponding author.
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.
Wang P, Zou F, Zhang X, Li H, Dulak A, Tomko RJ, Lazo JS, Wang Z, Zhang L,Yu J. MicroRNA-21 modulates G2/M checkpoint and cell cycle progression through Cdc25A. Cancer Res. 2009 Oct 15;69(20):8157-65.
Qiu W, Leibowitz B, Zhang L, Yu J. Growth factors protect intestinal stem cells from radiation-induced apoptosis by suppressing PUMA through the PI3K/AKT/p53 axis. Oncogene. 2010 Mar 18;29(11):1622-32.
Qiu W, Wang X, Leibowitz B, Liu H, Barker N, Okada H, Oue N, Yasui W, Clevers H, Schoen RE, Yu J*, Zhang L. Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20027-32. *Co-corresponding author.
Mustata G, Li M, Zevola N, Bakan A, Zhang L, Epperly M, Greenberger JS, Yu J*, Bahar I. Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death. Curr Top Med Chem. 2011;11(3):281-90. * Co-corresponding author.
Sun Q, Zheng X, Zhang L, Yu J. Smac Modulates Chemosensitivity in Head and Neck Cancer Cells through the Mitochondrial Apoptotic Pathway. Clin Cancer Res. 2011 Apr 15;17(8):2361-72.
Qiu W, Wu B, Wang X, Buchanan M, Regueiro MD, Hartman D, Schoen RE, Yu J, Zhang L. PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice. J Clin Invest. 2011 May 2;121(5):1722-32.
Leibowitz B, Qiu W, Liu H, Cheng T, Zhang L, Yu J. Uncoupling p53 functions in radiation-induced intestinal damage via PUMA and p21. Mol Cancer Res. 2011 May;9(5):616-25.
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