Serge Y. Fuchs. M.D., Ph.D.

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: 215 573-5188
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.

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 during viral infections and 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. Mechanistic studies on the function of SCF ubiquitin ligases that target ubiquitination of regulators of signal transduction and cell cycle
4. Translational studies aimed at the identification and characterization of small molecule modulators of downregulation of cytokine/hormone receptors and of activity of beta-Trcp E3 ubiquitin ligase activity.

Selected Publications

Lin DI, Barbash O, Suresh Kumar KG, Weber JD, Elledge SJ, Harper JW, Klein-Szanto AJP, Rustgi A, Fuchs SY, and Diehl JA (2006) Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF^{FBX4-αBcrystallin} complex, Mol Cell, 24: 355-66.

Suresh Kumar KG, Barriere H, Carbone CJ, Liu J, Swaminathan G, Xu P, Li Y, Baker DP, Peng J, Lukacs GL, and Fuchs SY (2007) Site-specific ubiquitination exposes a linear motif to promote interferon alpha receptor endocytosis, J Cell Biol, 179: 935-950.

Plotnikov A, Li Y, Tran TH, Tang W, Palazzo JP, Rui H and Fuchs SY (2008) Oncogene-mediated inhibition of glycogen synthase kinase 3? impairs degradation of prolactin receptor, Cancer Res, 68:1354-61

Suresh Kumar KG, Varghese B, Banerjee A, Baker DP, Constantinescu SN, Pellegrini S, and Fuchs SY (2008) Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif, J Biol Chem, in press

Varghese B, Barriere H, Carbone CJ, Banerjee A, Swaminathan G, Plotnikov A, Xu P, Peng J, Goffin V, Lukacs GL, and Fuchs SY (2008) Polyubiquitination of prolactin receptor stimulates its internalization, post-internalization sorting and degradation via the lysosomal pathway, Mol Cell Biol, in press

Search PubMed for more articles

Lab

Rotation Projects

Lab rotation projects are available in every main research area.

Lab 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
Christopher J. Carbone, Ph.D., Postdoctoral Fellow
Bentley Varghese, Graduate Student
Hui Zheng, Ph.D., Postdoctoral Fellow
Sabyasachi Bhattachariya, Ph.D., Postdoctoral Fellow
Juan Qiang, B.Sc., Research Specialist