Serge Y. Fuchs
Assistant Professor of Cell Biology, Dept of Animal Biology, School of Veteranary Medicine

Cancer Biology Program

Address

Room 316 Hill Pavilion
380 S University Avenue
Philadelphia, PA 19104-4539

Office tel.: 215 573-6949
Lab tel.: 215 573-6950
Fax: 215 746-2295
E-mail: syfuchs@vet.upenn.edu


EDUCATION

Yaroslavl State Medical School (Russia): MD, 1987.

All-Union Cancer Research Center, Academy of Medical Sciences (Russia): PhD (Experimental Oncology), 1992.

RESEARCH INTERESTS

• Aberrations of protein ubiquitination and degradation in cancer.

Key words: ubiquitin, ligase, proteolysis, cancer, cytokine, signal transduction.

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DESCRIPTION OF RESEARCH

Protein ubiquitination and degradation have emerged as important mechanisms in regulating cell growth and survival that play a key role in cancer. The long-term objective our laboratory is to identify the aberrations in ubiquitination of regulatory proteins that contribute to cell transformation and tumor progression and determine the usefulness of specific mediators of ubiquitination as potential targets for anti-cancer therapy. Our current focus is on the disregulated proteolysis of cytokine and hormone receptors in human malignant melanomas and breast cancers. For our studies, we employ various approaches and methods of molecular and cellular biology, biochemistry and mammalian genetics.

Main research areas:

1. Proteolysis of the interferon alpha receptor. This receptor plays an essential role in anti-tumorigenic, anti-viral and immunomodulatory effects of Type I IFN, which are often used in therapy of cancers, chronic viral infections and multiple sclerosis. We recently found that ligand-dependent down regulation of this receptor depends on its phosphorylation and ubiquitination by the beta-Trcp/HOS E3 ubiquitin ligase. This down regulation is accelerated in some human tumors including malignant melanomas. We are determined to understand the molecular mechanisms of IFNalpha receptor phosphorylation, ubiquitination, endocytosis and degradation as well as aberrations of these processes in cancers and the role of IFN receptor stability in the anti-tumorigenic effects of IFNalpha.
2. Proteolysis of the prolactin receptor that mediate cellular responses to hormone/cytokine prolactin, which is crucial for survival of human breast epithelial cells. Whereas degradation of prolactin receptor also involves specific phosphorylation, beta-Trcp-dependent ubiquitination and endocytosis, human breast cancer cells gain advantage in prolactin signaling by inhibiting the phosphorylation and degradation of its receptor. Investigation of the mechanisms of this inhibition and the role of increased stability of prolactin receptor in pathogenesis of breast cancer is currently underway.
3. 3. Identification of novel substrates for beta-Trcp E3 ubiquitin ligase and delineation of the mechanisms that regulate the activities of this ligase. Beta-Trcp levels and activities are often up-regulated in human cancers to ensue rapid proteolysis of proteins that negatively affect cell growth and survival (such as IkappaB, Emi1, etc). Conversely, the inhibition of beta-Trcp impairs growth and survival of human cancer cells. The ongoing delineation of the mechanisms regulating beta-Trcp activities and identification of its substrates may pave the road to targeting beta-Trcp for the therapeutic purposes.

RECENT PUBLICATIONS

Suresh Kumar K.G., Tang W., Ravindranath, A.R., Clark, W.A., Croze, E. and Fuchs, S.Y. (2003). SCF^HOS ubiquitin ligase mediates the ligand-induced down regulation of the interferon alpha receptor, EMBO J, 22, 5480-90.

2. Li, Y., Suresh Kumar, K.G., Tang, W., Spiegelman, V.S. and Fuchs, S.Y. (2004). Negative regulation of prolactin receptor stability and signaling mediated by SCF^β-TrCP E3 ubiquitin ligase. Mol Cell Biol, 24, 4038-4048.

Suresh Kumar, K.G., Krolewski, J.J. and Fuchs, S.Y. (2004). Phosphorylation and specific ubiquitin-acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of Type I interferon receptor. J Biol Chem. 279, 46614-46620.

Li, Y., Minkovsky, N., Suresh Kumar, K.G., Clevenger, C.V., Raghunath, P.N., Tomaszewski, J.E., Spiegelman, V.S., and Fuchs, S.Y. (2006). Stabilization of prolactin receptor in breast cancer cells. Oncogene. 25, 1896–902.

Noubissi, F., Elcheva, I., Bhatia, N., Shakoori, A., Ougolkov, A., Liu, J., Minamoto, T., Ross, J., Fuchs, S.Y., and Spiegelman, V.S. (2006). CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to beta-catenin signaling. Nature. 441, 898-901.

Lab

ROTATION PROJECTS

Lab rotation projects are available in every main research area.

Personnel:

• Serge Y. Fuchs, M.D., Ph.D. P.I.
• Jianghuai Liu, Ph.D., Postdoctoral Fellow
• Alex Plotnikov, Ph.D., Postdoctoral Fellow
• Wei-Chun HuangFu, Ph.D., Postdoctoral Fellow
• Gayathri Swaminathan, Ph.D., Postdoctoral Fellow
• Christopher J. Carbone, Ph.D., Postdoctoral Fellow
• Bentley Varghese, Graduate Student