Our research is aimed at understanding the mechanisms of tumor suppression. A longstanding research objective is to understand the molecular mechanisms of apoptosis. We focus on the central executioners of apoptosis, caspases, and their regulatory proteins. In recent years, we have also extended our study to the tumor suppressor p53, which induces apoptosis and other anti-proliferative processes in response to tumor-promoting stresses. Furthermore, the lab is investigating the mechanism of the promyelocytic leukemia protein nuclear bodies (PML-NBs). These proteinaceous organelles have a prominent role in tumor suppression and are also involved in other cellular processes including defense against viral infection and neurodegeneration.
Caspases dismantle cells by cleaving a large number of proteins essential for cell architecture and survival. Paradoxically, certain caspases are also required for cell proliferation. This dual role of caspase effectively links apoptosis with cell proliferation and helps maintain a homeostatic state. We pioneered a paradigm for the activation of caspases, whereby initiator caspase are activated by oligomerization. This finding provided a molecular framework for understanding the function of various apoptosis regulatory proteins. Subsequently, we defined an interdimer processing mechanism for oligomerization-induced activation of initiator caspases. The observation that a procaspase dimer, rather than a monomer, is the functional unit for activation defines a new mode for oligomerization-induced signal transduction, which enables the dimeric partners to take on separate roles of catalysis and regulation. For example, we have identified the innate ability of a proteolytically inactive caspase homologue, c-FLIPL, to promote caspase activation during apoptosis, and of a protease with limited similarity to caspases, the paracaspase MALT1, to promote caspase activation during proliferation, both through hetero-dimerization with caspase. More recently, we uncovered an important role of tRNA in apoptosis. tRNA binds to and inhibits the function of cytochrome c, an essential mediator of apopotosis. These findings reveal a previously unexpected intimate connection between two of the most ancient molecules in biology that impacts cell survival and metabolism, and provide a rationale for tRNA-based therapy for cancer.
p53 is a central hub in the cellular tumor suppression network. The principal antagonist of p53 is the oncogenic ubiquitin ligase Mdm2. Our work relates to the regulation of Mdm2. We found that Daxx, a multi-functional protein, is required for Mdm2 stability. Daxx functions as an adaptor bridging the deubiquitinating enzyme HAUSP/USP7 with Mdm2, leading to Mdm2 stabilization. Our finding indicates that the Daxx-Mdm2-Hausp complex is a focal point for regulating p53 activity under both stressed and unstressed conditions. Our work also relates to the role of p53 in cellular metabolism. Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production. This metabolic signature (the Warburg effect) permits rapid biosynthesis in tumor cells. We are investigating the mechanisms by which p53 regulates metabolic pathways and their dysregulation in tumor cells.
PML is a prototype of the tripartite (TRIM) motif-containing proteins, which are conserved in metazoans and quickly expanded during evolution with ~70 members in humans and mice. We show that TRIM proteins are SUMO E3s. The E3 activity depends on the TRIM motif, suggesting it to be the first widespread SUMO E3 motif. Our results greatly expand the number of identified SUMO E3s. Furthermore, TRIM E3 activity may be an important contributor to SUMOylation specificity and the versatile functions of TRIM proteins. We are further analyzing the biochemical function of the PML-NBs and the related TRIM proteins.
01. 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.
02. 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.
03. Kawadler H., Riley J. L., and Yang X. IThe paracaspase MALT1 control caspase-8 activation during lymphocyte proliferation. Mol Cell 31: 415-21, 2008.
04. 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.
05. Chu Y. and Yang X. SUMO E3 activity of TRIM proteins. Oncogene 30: 1108-16, 2011.
06. 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.
07. 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.
08. 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.
09. Ranaweera, R.S., and Yang X. Auto-ubiquitination of Mdm2 Enhances Its Substrate Ubiquitin Ligase Activity. J Biol Chem 288: 18939-46, 2013.
10. Guo L., Giasson B.I., Glavis-Bloom A., Gitler A.D., and Yang X. A cellular system that eliminates misfolded proteins and protects against neurodegeneration. Mol Cell Epub ahead of print, 2014.
Caitlin O'Neill - Administrative Assistant
Hongxia Hu - Postdoctoral Researcher
Liang Chen - Postdoctoral Researcher
Peng Jiang - Research Associate
Wenjing Du - Research Associate
Wil Prall - Lab Manager
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