Dermatology

DUMC 3135
Durham, NC 27710

919-684-6794

• PhD, University of Florida (1998)

• Postdoctoral Training, Immunology, University of California at San Francisco, (2000)
• Postdoctoral Training, Epithelial Biology and Cancer Biology, Stanford University (California), 2005

Epidermis of the skin undergoes lifelong self-renewal through a tight balance of cell growth, differentiation and programmed cell death. Deregulation of this balance is manifested in many diseases, including autoimmune diseases, psoriasis and cancer. Our lab is focused on addressing the following questions: 1) how are AP-1 family transcription factors involved in regulating human epithelial homeostasis and neoplasia? 2) how do NF-κB and JNK signaling pathways cross-talk to promote human squamous cell carcinoma (SCC)? and 3) What are the molecular mechanisms mediating the function of CYLD tumor suppressor in human SCC and melanoma?

I. Genetic regulation of epithelial cell proliferation and differentiation
NF-κB and AP-1 family gene regulatory proteins have been indicated in a wide range of cellular processes. Using both murine genetic and regenerated human skin tissue models, we have recently demonstrated that NF-κB and AP-1 regulate epidermal cell growth in an apposing fashion with the former inducing cell growth arrest and the later promoting cell proliferation. On the other hand, recent reports have revealed functional diversity for different AP-1 subunits. In particular, JunB and c-Jun AP-1 subunits have been implicated in a mouse model of psoriasis, while their role in human psoriasis remains controversial. Our goal is to use human skin tissue models to determine how JunB and c-Jun regulate epidermal cell proliferation and differentiation, and to explore their relevance to human skin diseases, including skin cancer and psoriasis.

II. Signaling networks in human SCC
Ras activation has emerged as a hallmark feature of a majority of human epidermal cancers, including SCC, the second most common malignancy in the United States.  In addition to Ras induction, IKK/NF-κB loss-of-function and JNK/AP-1 gain-of-function have been established in spontaneous human SCC. In order to study interactions between these dominant signaling cascades, we use multiplex serial gene transfer (MSGT) through which alterations in multiple signaling networks can be rapidly made in normal cells. Combined with tissue engineering, MSGT permits the molecular reconstruction of events sufficient to turn normal human tissues into cancer. These new genetic approaches have led to the finding that either NF-κB blockade or JNK induction is sufficient to act in conjunction with Ras activation to transform normal human epidermal cells directly into invasive neoplasia. Our current ongoing efforts are directed at 1) exploring the mechanisms governing the JNK signaling pathway in epidermal carcinogenesis; and 2) exploring therapeutic values of blocking JNK-AP1 signaling for human SCC.

III. CYLD in human SCC and melanoma
CYLD, a deubiquitinase, is initially identified as a tumor suppressor due to its autosomal dominant genetic linkage to skin appendage tumors collectively named Brook-Speigler Syndrome (BSS). The role of CYLD has been recently expanded to many other cancers, including melanoma, colon, liver, lung and renal and hematopoietic cancers. However, the underlying molecular mechanisms of CYLD in tumorigenesis are still unclear. Using transgenic mouse model, we have demonstrated that K14-driven epidermal specific expression of a catalytically deficient CYLD mutant (CYLDm) leads to increased sensitivity to chemically induced skin carcinogenesis. We have also found that CYLD is downregulated in human SCC and melanoma. Most importantly, restoring CYLD expression inhibits tumorigenesis of both SCC and melanoma. Currently, our efforts are directed at understanding 1) mechanisms mediating the CYLD expression, 2) the molecular mechanisms governing CYLD function in nonmelanoma and melanoma skin cancer.

http://dermatology.duke.edu/faculty/details/0380897

• Jin JY, Ke H, Hall RP, Zhang JY. c-Jun Promotes whereas JunB Inhibits Epidermal Neoplasia. J Invest Dermatol. 2011 Feb 3.  Abstract
• Miliani de Marval PL, Lutfeali SA, Jin Y, Leshin B, Selim MA and Zhang JY. CYLD control epidermal tumor growth and metastasis through JNK/AP1. (Cancer Prevention Research, Mar, in press, 2011)
  
    
• Ke H, Harris R, Coloff JL, Jin JY, Leshin B, Miliani de Marval P, Tao S, Rathmell JC, Hall RP, Zhang JY. The c-Jun NH2-terminal kinase 2 plays a dominant role in human epidermal neoplasia. Cancer Res. 2010 Apr 15;70(8):3080-8.  Abstract
• Adler AS, Sinha S, Kawahara, TL, Zhang JY, Segal E and Chang HA. Motif module map reveals enforcement of aging by continual NF-kB activity. Genes & Development 21:3244-57 2007.  
• Zhang JY, Adams AE, Ridky TW, Tao S, Khavari PA. Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia. Cancer Res. 2007 Apr 15;67(8):3827-34.  Abstract
• Zhang JY, Tao S, Kimmel R, Khavari PA. CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control.  J Cell Biol.  2005 Feb 14;168(4):561-6.  Abstract
• Zhang JY, Green CL, Tao S, Khavari PA. NF-kappaB RelA opposes epidermal proliferation driven by TNFR1 and JNK.  Genes and Development 18(1):17-22, 2004  Abstract
• Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Tao S, Lin Q, Kubo Y, Khavari PA. NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature. 2003 Feb 6;421(6923):639-43.  Abstract
• Hinata K, Gervin AM, Jennifer Zhang Y, Khavari PA. Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin. Oncogene. 2003 Apr 3;22(13):1955-64.  Abstract
• Lazarov M, Green CL, Zhang JY, Kubo Y, Dajee M, Khavari PA. Escaping G1 restraints on neoplasia--Cdk4 regulation by Ras and NF-kappa B. Cell Cycle. 2003 Mar-Apr;2(2):79-80.  Abstract
• Nagabhushanam V, Solache A, Ting LM, Escaron CJ, Zhang JY, Ernst JD. Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma. J Immunol. 2003 Nov 1;171(9):4750-7.  Abstract
• Zhang Y, Zhang P, West CM. A linking function for the cellulose-binding protein SP85 in the spore coat of Dictyostelium discoideum. J Cell Sci. 1999 Dec;112 ( Pt 23):4367-77.  Abstract
• Zhang Y, Brown RD Jr, West CM. Two proteins of the Dictyostelium spore coat bind to cellulose in vitro. Biochemistry. 1998 Jul 28;37(30):10766-79.  Abstract
• West CM, Mao J, van der Wel H, Erdos GW, Zhang Y. SP75 is encoded by the DP87 gene and belongs to a family of modular Dictyostelium discoideum outer layer spore coat proteins. Microbiology. 1996 Aug;142 ( Pt 8):2227-43.  Abstract