The laboratory investigates programmed cell death, a cellular process functioning to maintain tissue homeostasis and eliminate damaged or unwanted cells in multicellular organism. Programmed cell death plays crucial roles in development, immune responses, and many other physiological events. Malfunction of programmed cell death can lead to diseases such as cancer, immune disorders, and neurodegenerative diseases. We employ multiple approaches to study the molecular basis of programmed cell death. We also seek to translate our basic research findings into novel cancer therapies.
Currently, we are focusing on three topics:
Apoptosis is the major form of programmed cell death. It is executed by a subfamily of cysteine proteases known as caspases. During apoptosis, these “death executioners” are activated to attack a variety of cellular targets, and eventually lead to death of the host cells. A major caspase activation pathway in mammals is the intrinsic mitochondrial pathway. Critical for various biological events, this pathway is under close regulation in cells. Currently the lab is studying the mechanisms of such regulation. Further, using high throughput screening approach, we have identified a series of artificial small molecule modulators of this pathway, and are exploring their therapeutic potential.
Autophagy, a lysosome-dependent intracellular catabolic process, has emerged as a crucial component for regulating both apoptotic and non-apoptotic cell death. As such, autophagy is involved in various human diseases ranging from immune disorders, neurodegeneration, to cancer. Currently, we are investigating the molecular mechanisms of this complicated cellular process. Our mechanistic studies mainly focus on an autophagy-specific protein kinase complex known as ULK1-ATG13-FIP200 complex. This complex directly mediates the signaling of the nutrient-sensing kinase, mTOR, thus functioning as an interface linking autophagy with metabolism, cell growth, and cancer. We are also exploring the roles of autophagy in programmed cell death and cancer treatment.
PTEN is a potent tumor suppressor whose gene is mutated or deleted in various human cancers with a frequency as high as that of p53. Although PTEN is a master regulator for multiple cellular functions including cell growth, migration, and programmed cell death, how PTEN itself is regulated is not well-defined. Therefore, we are studying regulation of PTEN in context of programmed cell death. Our study indicates that (1) PTEN is regulated in a highly context-specific manner, and (2) different subcellular populations of PTEN can perform distinct biological function. Currently, we are investigating the regulatory mechanisms and therapeutic implication of PTEN under two specific, cancer-relevant contexts: hypoxia and IGF signaling.
Jiang X, Kim HE, Shu H, Zhao Y, Zhang H, Kofron J, Donnelly J, Burns D, Ng SC, Rosenberg S, Wang X. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003 Jan 10;299(5604):223-6.
Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007 Jan 12;128(1):129-39.
Ganley IG, Wong PM, Gammoh N, Jiang X. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell. 2011 Jun 24;42(6):731-43. doi: 10.1016/j.molcel.2011.04.024.
Feldman T, Kabaleeswaran V, Jang SB, Antczak C, Djaballah H, Wu H, Jiang X. A class of allosteric caspase inhibitors identified by high-throughput screening. Mol Cell. 2012 Aug 24;47(4):585-95. doi: 10.1016/j.molcel.2012.06.007. Epub 2012 Jul 12.
Gammoh N, Florey O, Overholtzer M, Jiang X. Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy. Nat Struct Mol Biol. 2013 Feb;20(2):144-9. doi: 10.1038/nsmb.2475. Epub 2012 Dec 23.
Louis and Allston Boyer Young Investigator Award for Basic Research, Memorial Sloan-Kettering Cancer Center (2007)
Scholar, American Cancer Society (2007-2010)
Catherine and Frederick Adler Chair for junior faculty, Memorial Sloan-Kettering Cancer Center (2006)
V Scholar, The V Foundation for Cancer Research (2004-2006 )
Alfred Bressler Scholar, Alref W. Bresller Scholars Fund (2004-2007)
Sigma Xi Award, UT Southwestern (1998)
Robert A. Welch Predoctoral Fellowship, UT Southwestern (1995-1999)
Xuejun Jiang heads a laboratory at the Sloan-Kettering Institute, where he continues to help unlock the mysteries of programmed cell death.
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