Our laboratory is interested in studying molecular pathways responsible for human tumorigenesis. In particular, we are examining molecular mechanisms that lead to the formation of synovial sarcoma, an aggressive tumor with a characteristic chromosomal translocation between chromosome 18 and X. This translocation generates a specific transforming oncoprotein, SYT-SSX. Understanding how this oncoprotein leads to the formation of synovial sarcoma will help us to design rational therapeutic interventions for this cancer as well as to expand our knowledge of molecular mechanisms of cancer in general. In addition, we are also interested in the signal transduction of Transforming growth factor ß (TGF-ß). TGF-ß is one of the most potent growth inhibitors capable of blocking proliferation of epithelial cells, the origin of majority of human tumors. Because TGF-ß can operate as an inhibitor of growth, TGF-ß signaling pathway has been implicated in the process of tumor suppression. Indeed, mutations inactivating TGF-ß signal transducers have been found in a variety of human cancers including those of pancreas and colon. We showed that TGF-ß signaling could also be abrogated through the activity of oncoproteins Ski/Sno, which directly interacted with Smad3 protein, an intracellular mediator of TGF-ß signaling. We discovered this connection through biochemical characterization of Smad3-interacting proteins followed by peptide sequence analysis through mass spectrometry. We will continue to examine TGF-ß signal transduction pathways that are involved in a variety of human diseases.

1. Y. Sun, D. Gao, Y. Liu, J. Huang, S. Lessnick and S. Tanaka (2006) IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Oncogene 25(7): 1042-52

2. X. Liu, Y. Sun, R. A. Weinberg and H. F. Lodish. (2001) Ski/Sno and TGF-ß Signaling. Cytokine & Growth Factor Reviews. 12(1):1-8

3. X. Liu, Y. Sun, M. Ehrlich, T. Lu, X, Hua, Y. Kloog, R. A. Weinberg, H. F. Lodish and Y. I. Henis. (2000) Loss of TGF-ß Growth Inhibitory Response by Oncogenic Ras is Linked to Alterations in the Subcellular Localization of p27. Oncogene 19(51): 5926-35

4. Liu X, Constantinescu SN, Sun Y, Bogan JS, Hirsch D, Weinberg RA, Lodish HF. (2000) Generation of mammalian cells stably expressing multiple genes at predetermined levels. Anal Biochem. 10, 20-28.

5. Sun, Y., Liu, X., Eaton, E. N., Lodish, H. F. and Weinberg, R. A. (1999) SnoN and Ski protooncoproteins are rapidly degraded in response to TGF-ß signaling. Proc. Natl. Acad. Sci. U S A 96, 12442-12447.

6. Sun, Y.,* Liu, X.,* Eaton, E. N., Lane, W. S., Lodish, H. F. and Weinberg, R. A. (1999) Interaction of the Ski Oncoprotein with Smad3 Regulates TGF-ß Signaling. Molecular Cell 4, 499-509. (* equal co-first author)

7. Wells, R. G., Gilboa, L., Sun, Y., Liu, X., Henis, Y. I., and Lodish, H. F. (1999). Transforming growth factor-beta induces formation of a dithiothreitol-resistant type I/Type II receptor complex in live cells. J Biol Chem 274, 5716-22.

8. Liu, X., Sun, Y., Constantinescu, S. N., Karam, E., Weinberg, R. A., and Lodish, H. F. (1997). Transforming growth factor beta-induced phosphorylation of Smad3. Proc Natl Acad Sci U S A 94, 10669-74.

9. Wanker, E. E.,* Sun, Y.,* Savitz, A. J., and Meyer, D. I. (1995). Functional characterization of the 180-kD ribosome receptor in vivo. J Cell Biol 130, 29-39. (* equal co-first author)

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