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BIOCHEMISTRY
 
 

Dr. Yu-Chung Yang

Professor

Pub Med:

Dr. Yu-Chung Yang

We are interested in studying: (1)cytokine signal transduction,
(2) transcriptional regulation,
(3) hematopoiesis, and
(4) developmental biology and its relevance to diseases.

The molecular cloning of many cytokines made it possible to define the biological activities of these factors, now recognized as playing crucial roles in immunity, cell growth and differentiation, and also whether aberrant or damaged cells live or die. These observations led to translational studies and ultimately to clinical trials, which have shown that cytokines have great potential in the treatment of many diseases, including cancer. Since cytokines possess common and unique biological functions, a clear understanding of how each cytokine works (a process referred to as signal transduction) is crucial in order to know the uses to which each cytokine may be put and also how to use the cytokines most effectively in combination therapies. Continued basic research on cytokine signal transduction will also provide new insights into mechanisms that regulate cell growth, differentiation, and survival, which is important to our understanding of the initiation, progression and spread of cancer. Recent work has focused on biochemical and functional aspects of several transcription factors and transcription cofactors. The laboratory cloned Cited2 in 1998 and showed that Cited2 is induced by many biological stimuli such as cytokines, serum and LPS in different cell types and it is a transforming gene when overexpressed. They generated Cited2 knockout mice and showed that deletion of Cited2 causes Cited2-/- embryos to die at mid- to late gestation with many developmental defects. Since ectopic activation of the signaling pathways that control normal development and homeostasis could lead to hyperproliferative conditions, such as cancer, studies are now underway to generate tissue-specific knockout mouse models to study the role of Cited2 in normal and stressed physiological conditions and their dysregulation in disease processes including cancer.

Dr. Yang and her former colleagues at Genetics Institute were responsible for the cloning of three cytokines: human interleukin (IL)-3, -9 and -11**. FDA approved IL-11 in 1997 for treating cancer patients with severe chemotherapy-induced thrombocytopenia. It is the first thrombopoietic agent to be approved for clinical use in the United States. It is anticipated that understanding the molecular basis of cytokine signal transduction and cellular responses may lead to new modalities of treatment for various diseases including cancer.

Selected References

  • Yin, Z., Haynie, J., Yang, X., Han, B., Kiatchoosakun, S., Restivo, J., Yuan, S., Prabhakar, N., Herrup, K., Conlon, R., Hoit, B., Watanabe, M., and Yang, Y-C.: Essential role of Cited2, a negative regulator for HIF-1a, in heart development and neurulation. Proc. Natl. Acad. Sci. USA, 99: 10488-10493, 2002.

  • Xiao, H., Chung, J., Kao, H-Y., and Yang, Y-C.: Tip60 is a co-repressor for STAT3. J. Biol. Chem., 278:11197-204, 2003.

  • Yin, Z., Haynie, J., Williams, B., and Yang, Y-C.: C114 is a novel IL-11-inducible nuclear dsRNA-binding protein that inhibits Protein Kinase R. J. Biol. Chem., 278:22838-45, 2003.

  • Zheng, G., and Yang, Y-C.: ZNF76, a novel transcriptional repressor targeting TBP, is modulated by sumoylation. J. Biol. Chem., 279:42410-42421, 2004.

  • Zheng, G., and Yang, Y-C.: Sumoylation and acetylation play opposite roles in transactivation of PLAG1 and PLAGL2. J. Biol. Chem., 280:40773-40781, 2005.

  • Zheng, G., and Yang, Y-C.: Acetylation and alternative splicing regulate ZNF76-mediated transcription. Biochem. Biophys. Res. Comm., 339:1069-1075, 2006.

  • Chou, Y-T., Wang, H., Chen, Y., Danielpour, D., and Yang, Y-C.: Cited2 modulates TGF-b mediated up-regulation of MMP9. Oncogene, 25, 5547-60, 2006.

  • Chou, Y-T., and Yang, Y-C.: Posttranscriptional control of Cited2 by TGF-b: regulation via Smads and Cited2 coding region. J. Biol. Chem. 281:18451-62, 2006.

  • Xu, B., Doughman, Y-Q., Turakhia, M., Jiang, W., Landsettle, C., Agani, F., Semenza, G.L., Watanabe, M., and Yang, Y-C.: Partial rescue of defects in Cited2-deficient embryos by HIF-1a heterozygosity Dev. Biol. 301:130-40, 2007.

  • Zhang, K., Zheng, G., Yang, Y-C.: Stabilization of Nmi Protein through Its Interaction with Tip60. Mol. Cell. Biochem., 303: 1-8, 2007.

  • Ning, J., Zheng, G., and Yang, Y-C.: Tip60 modulates PLAGL2-mediated transactivation by acetylation. Journal of Cellular Biochemistry, in press.

  • Chen, Y., Haviernik P., Bunting, K.D., and Yang, Y-C.: Cited2 is required for normal hematopoiesis in the murine fetal liver. Blood, 110: 2889-98, 2007.

  • Qu X., Lam E., Doughman Y-Q, Chen Y., Chou Y-T, Lam M, Turakhia M, Dunwoodie SL, Watanabe M, Xu B, Duncan SA, Yang Y-C.: Cited2, a novel coactivator for HNF4alpha, is essential for liver development. EMBO J., 26(21):4445-56, 2007.

  • Zheng, G., Ning, J., and Yang, Y-C.: PLAGL2 controls the stability of Pirh2, an E3 ubiquitin ligase for p53. BBRC, 364(2):344-50, 2007.