Immunology Graduate Group
Xiaolu Yang, Ph.D.
Associate Professor, Department of Cancer Biology
Address: Room 610 BRB II/III
Office Phone: (215) 573-6739
Lab Phone: (215) 573-4625
Fax: (215) 573-6725
Email: xyang@mail.med.upenn.edu
Education:
Ph.D., Columbia University
B. Sc., Tsinghua University (China)
Research Interests
Molecular mechanisms of apoptosis and how they may relate to cancer and other diseases.
Research Summary
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 lymphocyte 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.
Recent Publications
J. Tang, L. Qu, J. Zhang, W. Wang, J. S. Michaelson, Y. Y. Degenhardt, W. S. El-Deiry, and X. Yang (2006) Critical role for Daxx in regulating Mdm2. Nature Cell Biology 8: 855-62.
S. Hu, M.Q. Du, S.M. Park, A. Alcivar, L. Qu, S. Gupta, J. Tang, M. Baens, H. Ye, T.H. Lee, P. Marynen, J.L. Riley, X. Yang (2006) cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas. J Clin Invest. 116:174-181.
J. Tang, S. Wu, H. Liu, R. Stratt, O. G. Barak, R. Sheikhattar, D. J. Picketts, X. Yang (2004) A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. J. Biol. Chem. 279: 20369-20377.
D. W. Chang, Z. Xing, V.L. Capacio, M. E. Peter and X. Yang (2003) Interdimer processing mechanism of procaspase-8 activation. EMBO J. 22:4132-4142.
D. W. Chang, Z. Xing, Y. Pan, A. Algeciras-Schimnich, B. C. Barnhart, S.Yaish-Ohad, M. E. Peter and X. Yang (2002) c-FLIP(L) is a dual function molecule for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 21:3704-3714.