Songyun Zhu, M.S., M.D.
Senior Researcher
Johnathan Hall, Ph.D.
Postdoctoral Research Associate
Rakesh Ranjan
Graduate Student
John House
Graduate Student
Jeanne Burr
Research Assistant
Mailing
address:
Department of Environmental
and Molecular Toxicology
Box 7633, NC State University
Raleigh, NC 27695-7633
Shipping
address:
Suite 1104, 850 Main Campus Dr.
Raleigh, NC 27606
Phone
919.515.2274
Fax 919.515.7169
Robert C. Smart, PhD
Professor
Director of Graduate Programs
Coordinator, M
Molecular & Cellular Toxicology
Cell Signaling and Cancer Group
Phone: 919-515-7245
E-mail: robert_smart@ncsu.edu
Education
BS, University of Massachusetts at Dartmouth
PhD, University of Michigan
Postdoctoral, Roche Institute of Molecular Biology
Research Interests of the Cell Signaling and Cancer Group
Cancer susceptibility is determined by complex interactions between age, environment and an individual's genetic make-up. We are interested in the interplay between the environment and genetics in carcinogenesis. More specifically we are focused on the identification and characterization of genes/signaling pathways that are determinants of susceptibility or resistance to tumorigenesis. We have focused our efforts on specific members of the C/EBP family of transcription factors because of their known and emerging roles in differentiation, senescence, apoptosis, cell cycle regulation and cancer pathogenesis. In terms of epithelial cancer pathogenesis, our laboratory has identified C/EBPβ as a susceptibility gene and C/EBPα as a resistance gene or suppressor. Current studies in the laboratory are aimed at the elucidation of the; (1) role of C/EBPα and C/EBPβ in the regulation of epithelial cell proliferation, differentiation, apoptosis and cancer, (2) role of C/EBPs in DNA damage response including checkpoints and DNA repair, (3) the signaling pathways involving oncogenes including Ras and receptor tyrosine kinases that control the transcription activity and levels of C/EBPs. The laboratory is active in the development and use of genetically modified mice to characterize the function of genes involved in cancer susceptibility and normal cellular processes. The laboratory utilizes the mouse skin model of multistage carcinogenesis, a well-defined model of epithelial neoplasia.
Selected Publications
- Oh, H. S. and R. C. Smart. Expression of CCAAT/enhancer binding proteins (C/EBP) is associated with squamous differentiation in epidermis and isolated primary keratinocytes and is altered in skin neoplasia. J. Invest. Dermatol. 110 : 101-107. 1998
- Owens, D. M., S-J. C. Wei and R. C. Smart. A multihit, multistage model of chemical carcinogenesis. Carcinogenesis 20 : 1837-1844. 1999
- Zhu, S., H. S. Oh, M. Shim, E. Sterneck, P. F. Johnson and R. C. Smart.C/EBP modulates the early events of keratinocyte differentiation involving growth arrest, keratin 1 and keratin 10 expression. Mol. Cell. Biol. 19 : 7181-7190. 1999
- Wang, H. Q. and R. C. Smart. Overexpression of protein kinase C-a in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2, and TNF-a but not tumor promotion. J.Cell Sci. 112 : 3497-3506. 1999
- Wang, H. Q., M. P. Kim, H. F. Tiano, R. Langenbach and R. C. Smart.Protein kinase C-a coordinately regulates cytosolic phospholipase A2 activity and the expression of cyclooxygenase-2 through different mechanisms in mouse keratinocytes. Mol. Pharmacol. 59 : 860-866. 2001
- Zhu, S., K. Yoon, E. Sterneck, P. F. Johnson and R. C. Smart . CCAAT/enhancer binding protein-b (C/EBPβ) is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling. Proc. Natl. Acad. Sci. USA 99 : 207-212. 2002
- Tiano, H. F., C, Loftin, J. Akunda, J. Spalding, A. Sessoms, D. Dunson, E. Rogin, S. Morham, R.C. Smart, and R. Langenbach. Deficiency of either cyclooxygenase 1 or cyclooxygenase 2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res 62 : 3395-3401. 2002
- Shim, M. and R. C. Smart. Lithium stabilizes the CCAAT/enhancer-binding protein alpha (C/EBPα) protein through a glycogen synthase kinase 3 (GSK3)-independent pathway involving direct inhibition of proteasomal activity. J. Biol. Chem. 278 : 19674-19681. 2003
- Shuman, J. D., T. Sebastian, P. Kaldis, T. D. Copeland, S. Zhu, R.C. Smart and P. J. Johnson. Cell cycle-dependent phosphorylation of C/EBPβ mediates oncogenic cooperativity between C/EBPβ and H-RasV12. Mol. Cell. Bio. 24 : 7380-7391. 2004
- Yoon, K. and R. C. Smart. CCAAT/enhancer binding protein-alpha is a DNA-damage inducible p53-regulated mediator of the G1 checkpoint. Mol. Cell. Bio. 24 : 10650-10660. 2004
- Shim, M., K. L. Powers, S. J. Fry, S. Zhu and R. C. Smart .Diminished expression of C/EBPα in skin carcinomas is linked to oncogenic Ras and re-expression of C/EBPα in carcinoma cells inhibits proliferation. Cancer Res, 65 : 861-867. 2005
- Sterneck, E., S. Zhu, A. Ramierz, J. L. Jorcano and R. C. Smart. Conditional ablation of C/EBPβ demonstrates its keratinocyte specific requirement for cell survival and mouse skin tumorigenesis. Oncogene 25 :1272-1276. 2006.
- Omori, E., K. Matsumoto, H. Sanjo, S. Sato, S. Akira, R. C. Smart, and J. Ninomiya-Tsuji TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis J. Biol. Chem. 281 : 19610-19617. 2006.
- Yoon, K., S. Zhu, S. J. Ewing and R. C. Smart. Decreased survival of C/EBPβ -deficient keratinocytes is due to aberrant regulation of p53 levels and function. Oncogene 26 : 360-367. 2007.
- Loomis, K. D., S. Zhu, K. Yoon, P. F. Johnson and ,R. C. Smart .Genetic ablation of C/EBPα in epidermis reveals its role in suppression of epithelial tumorigenesis. Cancer Res 67 : 6768-76 2007
- Ewing, S. J., S. Zhu, F. Zhu, J. S. House and R. C. Smart. C/EBPβ represses p53 to promote cell survival downstream of DNA damage independent of oncogenic Ras and p19Arf. Cell Death and Diff 15 : 1734-1744 2008
- Ranjan, R., E. A. Thompson, K. Yoon, R. C. Smart. C/EBPα expression is partially regulated by C/EBPβ in response to DNA damage and C/EBPα-deficient fibroblasts display an impaired G1 checkpoint. Oncogene [Epub ahead of print].