Inflammation
Our recent studies show that CCN proteins can profoundly influence the activities of inflammatory cytokines of the tumor necrosis factor (TNF) family. TNFa is a potent activator of NFkB, which induces a pro-inflammatory and anti-apoptotic program. Thus, although TNFa is a well characterized apoptotic inducer, it can induce apoptosis only when NFkB signaling or de novo protein synthesis is blocked, and how it triggers apoptosis in vivo is not well understood. Surprisingly, CCN1 can unmask the apoptotic activity of TNFa without perturbation on NFkB signaling, thereby limiting the inflammatory response in microenvironments where CCN1 is expressed. Furthermore, mice with the genomic Ccn1 locus replaced with an apoptosis-defective Ccn1 allele are severely blunted in TNFa-induced apoptosis, indicating that CCN1 is a true physiologic regulator of TNFa cytotoxicity. We are currently investigating how TNFa- and CCN1-induced signaling pathways converge, and how TNFa/CCN1 synergism regulates inflammatory and disease processes.
Cancer
Our laboratory has established that CCN proteins (CCN1, CCN2, and CCN3) are potent angiogenic inducers in vivo. The angiogenic activity of CCNs may play a critical role in the observed strong association of CCN expression in cancers of several tissues, including the breast, glia, and pancreas. In these cancers, CCN1 is synthesized either by the cancer cells or as a result of the interaction between cancer cells and the stroma. We are analyzing the contribution of CCN1-regulated angiogenesis in the context of tumor growth, using allelic replacement and transgenic mouse models.
Cardiovascular Development
The significance of Ccn1 in cardiovascular development is demonstrated by the phenotypes of Ccn1-null mice, which suffer embryonic lethality due to impaired vessel bifurcation, loss of vessel integrity, and defective cardiac atrioventricular valvuoseptal morphogenesis. Heterozygous Ccn1 mice are largely viable, but exhibit ostium primum atrial septal defects with incomplete penetrance. We are currently studying the roles of Ccn1 in cardiovascular development and cardiovascular diseases.
Selected Recent Publications:
C.-C. Chen, Young, J.L., Monzon, R.I., Chen, N., Todorovic, V., and Lau, L.F. (2007) Cytotoxicity of TNFa is regulated by integrin-mediated matrix signaling. EMBO J. 26:1257-1267.ABSTRACT
Mo, F.-E and Lau, L.F. (2006) The matricellular protein CCN1 is essential for cardiac development. Circulation Res. 99: 961-969 ABSTRACT.
Todorovic, V., Chen, C.-C., Hay, N., and Lau, L.F. (2005) The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts. J. Cell Biol. 171: 559-568 ABSTRACT.
Lau, L.F. and Lam, S.C.-T. (2005) Integrin-mediated CCN functions. In "CCN proteins: a new family of cell growth regulators," B. Perbal and M. Takigawa, Editors. Imperial College Press, UK. pp.61-79.
Jin, Y., Kim, H.P., Ifedigbo, E., Lau, L.F., and Choi, A.M. (2005) Cyr61 Protects against Hyperoxia-Induced Cell Death via Akt Pathway in Pulmonary Epithelial Cells. Am J. Respir. Cell Mol Biol. 33: 297-302.
Zhang, W., Swanson, R., Izaguirre, G., Xiong, Y., Lau, L.F., and Olson, S.T. (2005) The heparin binding site of antithrombin is crucial for antiangiogenic activity. Blood 106: 1621-1628.
Lin, C.G., Chen, C.C., Leu, S.J., Grzeszkiewicz, T.M., and Lau, L.F. (2005) Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing. J Biol Chem. 280: 8229-37.
Lapik, Y.R., Fernandes, C.J., Lau, L.F., and Pestov, D.G. (2004) Physical and functional interaction between Pes1 and Bop1 in mammalian ribosome biogenesis. Molecular Cell 15: 17-29.
Leu, S.J., Chen, N., Chen, C.C., Todorovic, V., Bai, T., Juric, V., Liu, Y., Yan, G., Lam, S.C., and Lau, L.F. (2004) Targeted mutagenesis of the angiogenic protein CCN1 (CYR61): selective inactivation of integrin a6b1-heparan sulfate proteoglycan coreceptor-mediated cellular functions. J. Biol. Chem. 279: 44177-44187.
Chen, N., Leu, S.J., Todorovic, V., Lam, S.C., and Lau, L.F. (2004) Identification of a novel integrin avb3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells. J. Biol. Chem. 279: 44166-44176.
Zhang, W., Chuang, Y.J., Swanson, R., Li, J., Leung, L., Lau, L.F., and Olson, S.T. (2004) Anti-angiogenic antithrombin downregulates the expression of the pro-angiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells. Blood, 15: 1185-1191.
Former Graduate
Students of the Lau Lab
Ian J. Davis, M.D. Ph.D., Assistant Professor, University of North Carolina at Chapel Hill, NC (Web page)
Branko V. Latinkic, Ph.D., Lecturer, Cardiff University, UK. (Web page)
Shr-Jeng Leu, Ph.D., Assistant Professor, National Yang Ming University, Taiwan (Web page)
Fan-E Mo, Ph.D., Assistant Professor, National Cheng Kung University, Taiwan (Web page)
Timothy P. O’Brien, Ph.D., Associate Professor, Cornell University, NY. (Web page)
Dimitri G. Pestov, Ph.D., Assistant Professor, University of Medicine and Dentistry of New Jersey (Web page)
George P. Yang, M.D., Ph.D., Assistant Professor, Stanford University, CA (Web page)
Jeong Kyo Yoon, Ph.D., Principal Investigator, Maine Medical Center Research Institute, ME (Web page)
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