Chao-Lan Yu, Ph.D.
Assistant Professor of Molecular Physiology & Biophysics
Vanderbilt University Medical Center
813B Light Hall
Nashville, TN 37232-0615
Regulation of the JAK-STAT signaling pathway and gene expression in cellular transformation.
The family of Janus protein tyrosine kinases (JAKs) and the downstream signal transducers and activators of transcription (STATs) are essential for cytokine/growth factor signaling and play critical roles in modulating many important physiological functions. Our earlier studies further demonstrated their possible involvement in cellular transformation and in human cancer. We hypothesize that disregulation of distinct JAK-STAT pathway, especially STAT3 and STAT5, may contribute to certain types of oncogenesis. Our research currently focuses on the negative regulation of the JAK-STAT pathway and how its disruption may lead to tumorigenesis. Using cytokine-dependent T cell lines, we have recently shown that STAT5 activation can be inhibited by proteasome-mediated protein degradation and by protein tyrosine phosphatase SHP-2. We will continue to explore the detailed mechanisms of these regulations in normal and transformed cells. In the future, we also plan to expand our studies in three other major directions. First, we will perform proteomic analysis to identify novel interacting partners in regulating the JAK-STAT pathway. Second, we will use genomic approach to characterize important STAT-target genes. Third, we will establish animal models to address the biological outcome of modulating the JAK-STAT pathway.
- Mingjian Shi, John C. Cooper, and Chao-Lan Yu A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through STAT5B activation. Molecular Cancer Research, 4(1), 39-45, 2006.
- John C. Cooper, Jared N. Boustead and Chao-Lan Yu Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS). Cellular Signalling, 18(6), 851-860, 2006.
- Michael Wei-Chih Su, Saiju Pyarajan, Jin-Hong Chang, Chao-Lan Yu, Yong-Jiu Jin, York-Dieter Stierhof, Peter Walden, Steven J. Burakoff Fratricide of CD8+ cytotoxic T lymphocytes is dependent on cellular activation and perforin-mediated killing. European Journal Of Immunology, 34(9), 2459-2470, 2004.
- Tkaczuk, J., Yu, C.-L., Baksh, S., Milford, E.L., Carpenter, C.B., Burakoff, S.J., and McKay, D.B Effect of anti-IL-2Ralpha antibody on IL-2-induced Jak/STAT signaling. Am. J. Transplant., 2(1), 31-40, 2002.
- Tkaczuk, J., Milford, E., Yu, C.-L., Baksh, S., Carpenter, C., Burakoff, S.J., and McKay, D.B Intracellular signaling consequences of anti-IL-2Ra blockade by Daclizumab. Transplant. Proc., 33(1-2), 212-3, 2001.
- Su, M.W.-C., Yu, C.-L., Burakoff, S.J., and Jin, Y.-J Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3-induced T cell activation. J. Immunol., 166(6), 3975-82, 2001.
- Yu, C.-L., Jin, Y.-J., and Burakoff, S.J Cytosolic tyrosine dephosphorylation of STAT5: Potential role of SHP-2 in STAT5 regulation. J. Biol. Chem., 275(1), 599-604, 2000.
- McKay, D.B., Tao, L., Yu, C.-L., and Burakoff, S.J Alloantigen-unresponsiveness results in defects in intracellular signaling and transcriptional activation of the IL-2 promoter. Transplant., 67S406, 1999.
- Jin, Y.-J., Yu, C.-L., and Burakoff, S.J Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal structure and catalytic activity. J. Biol. Chem., 274(40), 28301-7, 1999.
- Stofega, M.R., Yu, C.-L., Wu, J., and Jove, R Activation of extracellular signal-regulated kinase (ERK) by mitogenic stimuli is repressed in v-Src-transformed cells. Cell Growth Differ., 8(1), 113-9, 1997.
- Campbell, G.S., Yu, C.-L., Jove, R., and Carter-Su, C Constitutive activation of JAK1 in Src-transformed cells. J. Biol. Chem., 272(5), 2591-4, 1997.
- Garcia, R., Yu, C.-L., Hundall, A., Nelson, K.L., Smithgall, T., Fujita, D.J., Ethier, S.P., and Jove, R Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ., 8(12), 1267-76, 1997.
- Yu, C.-L., Jove, R., and Burakoff, S.J Cutting edge: constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase. J. Immunol., 159(11), 5206-10, 1997.
- Yu, C.-L. and Burakoff, S.J Involvement of proteasomes in regulating Jak-STAT pathways upon interleukin-2 stimulation. J. Biol. Chem., 272(22), 14017-20, 1997.
- Sartor, C.I., Dziubinski, M.L., Yu, C.-L., Jove, R., and Ethier, S.P Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. Cancer Res., 57(5), 978-87, 1997.
- Yu, C.-L., Meyer, D.J., Campbell, G.S., Larner, A.C., Carter-Su, C., Schwartz, J., and Jove, R Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science , 269(5220), 81-3, 1995.
- Yu, C.-L., Prochownik, E.V., and Jove, R Proximal promoter region of the junB gene mediates attenuation of serum inducibility in Src transformed cells. Cell Growth Differ., 6(12), 1513-21, 1995.
- Yu, C.-L., Prochownik, E.V., Imperiale, M.J., and Jove, R Attenuation of serum inducibility of immediate early genes by oncoproteins in tyrosine kinase signaling pathways. Mol. Cell. Biol., 13(4), 2011-9, 1993.
- Apel, I., Yu, C.-L., Wang, T., Dobry, C., Van Antwerp, M.E., Jove, R., and Prochownik, E.V Regulation of the junB gene by v-src. Mol. Cell. Biol., 12(8), 3356-64, 1992.