Xiaolu Yang

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Professor of Cancer Biology
Department: Cancer Biology

Contact information
421 Curie Boulevard
University of Pennsylvania School of Medicine
Philadelphia, PA 19104-6160
Office: (215) 573-6739
Fax: (215) 573-6725
B.Sc. (Physical Chemistry)
Tsinghua University, Beijing, China, 1985.
M.Phil. (Genetics & Development)
Columbia University, New York, NY, 1992.
Ph.D. (Genetics & Development)
Columbia University, New York, NY, 1994.
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Description of Research Expertise

Research Interests
Molecular mechanisms of apoptosis and how they may relate to cancer and other diseases.

Key words:
Cancer, Apoptosis, Caspases, IAP, Daxx, Mdm2, p53

Description of Research
Programmed cell death or apoptosis is a physiological process of cell auto-destruction that eliminates unwanted, damaged, or harmful cells. Dysregulation of apoptosis is associated with many devastating diseases such as cancer, neurodegeneration, and immunodeficiency. Our research goal is to understand the molecular mechanisms of apoptosis in the hope that this insight may lead to new directions for therapeutic interventions. Our current projects are focused on three areas: caspases and their regulatory proteins, the p53 system, and promyelocytic leukemia protein nuclear bodies (PML-NBs).

Caspases are the central executioners of apoptosis. These proteases are synthesized as latent precursors and become activated during apoptosis. Active caspases cleave a large number of regulatory and structural proteins, thus dismantling the cells. Activation of caspases is tightly regulated. We previously pioneered a paradigm for the activation of caspases, whereby initiator caspase activation is controlled by adaptor-mediated oligomerization. We are further investigating the mechanisms of caspase activation in various apoptosis pathways. Paradoxically, some caspases are also required for cell proliferation. We are studying the proliferative role of caspases to better understand the interplay between cellular life and death processes.

Caspases are regulated by the inhibitor-of-apoptosis proteins (IAPs). In addition, several IAPs are also E3 ubiquitin ligases that mediate the ubiquitination and degradation of an increasing number of cellular proteins. We are investigating the function of IAPs by identifying and characterizing their targets. Our recent study has revealed that cellular IAP 2 (cIAP2) is an inhibitor for lymphocyte proliferation and this function is impaired in lymphomas.

The p53 system is crucial for tumor suppression. p53 induces apoptosis and other anti-proliferative processes in response to diverse stresses such as DNA damage and activation of oncogenes; it prevents cells carrying a damaged genome or other cancer promoting alterations from replicating. Nearly half of all human tumors harbor mutations in p53 itself, and the rest often have alternations in p53 regulators and/or effectors. In unstressed cells, the potent anti-proliferative function of p53 is restrained by the E3 ligase Mdm2, while in stressed cells Mdm2 mediates self-degradation, allowing for p53 activation. We recently found that the differential regulation of the Mdm2-mediated self-degradation and p53 degradation involves an adaptor protein called Daxx. We are further investigating the regulation of the p53 system.

The PML-NBs are subnuclear organelles that modulate a range of fundamental cellular processes including apoptosis, cellular senescence, transcription, DNA damage signaling, and anti-viral responses. Disruption of PML-NBs is associated with tumorigenesis, viral infection, and neurodegeneration. The molecular and biochemical function of the PML-NBs remains enigmatic. PML-NBs contain a large number of proteins including p53 and Daxx. We are investigating the mechanism of PML-NBs’ action.

Lab personnel:
Wenjing Du, Postdoctoral Researcher
Alexander Glavis-Bloom, Research Specialist
Peng Jiang, Postdoctoral Researcher
Caitlin O'Neill, Administrative Assistant
Joy Wang Ph.D. Student
Lynn Wang, Ph.D. Student

Selected Publications

Du W., Jiang P., Mancuso A., Stonestrom A., Brewer M.D., Minn A.J., Mak T.W., Wu M., and Yang X: TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Bio 15: 991-1000, 2013 Notes: Cover story and commented on in this issue.

Jiang P., Du W., Mancuso A., Wellen K. and Yang X.: Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493: 689-93, 2013.

Jiang P., Du W., Wang X., Mancuso A., Gao X., Wu M., and Yang X.: p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 13: 310-18, 2011 Notes: cover story and commented on in this issue.

Chu Y. and Yang X.: SUMO E3 activity of TRIM proteins. Oncogene 30: 1108-16, 2011.

Mei Y., Yong J., Liu H., Shi Y., Meinkoth J., Dreyfuss G., and Yang X.: tRNA binds to cytochrome c and inhibits caspase activation. Mol Cell 37: 668-78, 2010 Notes: Cover story and commented on in this issue. Highlighted in Science Signaling and Chemical & Engineering News.

Kawadler H., Riley J. L., and Yang X.: The paracaspase MALT1 control caspase-8 activation during lymphocyte proliferation. Mol Cell 31: 415-21, 2008 Notes: Highlighted in Science Signaling.

Tang J., Qu L., Zhang J., Wang W., Michaelson J. S., Degenhardt Y., El-Deiry W.S., and Yang X.: Critical role for Daxx in regulating Mdm2. Nat Cell Biol. 8: 855-62, 2006 Notes: Commented on in this issue.

Hu S., Du M.-Q., Park S.-M., Alcivar A., Qu L., Gupta S., Tang J., Baens M., Ye H., Lee T., Marynen P., Riley J.L., and Yang X.: cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas. J Clin Invest. 116: 174-81, 2006 Notes: Commented in this issue.

Yang X., Chang H.Y., and Baltimore D.: Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Science 281: 1355-7, 1998.

Yang X., Chang H.Y., and Baltimore D.: Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1: 319-25, 1998.

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Last updated: 04/10/2014
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