Welcome to Jennifer Zhang's lab homepage. Our lab is in the Department of Dermatology and is located in the School of Medicine at Duke University .

Research:

Epidermis, the outermost layer of our body, is comprised of stratified epithelial cells and undergoes life-long self renewal through a tight balance of cell proliferation and programmed cell death. This balancing process is regulated by a complex array of transcription factors and their upstream signaling molecules. Our lab uses skin as a model system for organogenesis to study 1) genetic regulatory mechanisms involved in epithelial proliferation and differentiation and 2) signaling networks in epidermal carcinogenesis. Our current study is focused on investigating molecular components of the two major signaling cascades, including IKK/NF-kB and JNK/AP1 signaling pathways, in epidermal growth and neoplasia.

I. Genetic regulation of epidermal proliferation

NF-kB and AP1 family gene regulatory proteins have been indicated in a wide range of cellular processes. Our recent findings using both murine genetic and regenerated human skin tissue models indicated that NF-kB and AP1 regulate epidermal cell growth control in an opposing fashion with the former induces cell growth arrest. Our current efforts are directed at: 1) characterization of cross-talk between the upstream signaling molecules of NF-kB and AP1 proteins in epidermal growth control, and 2) identification of AP1 down stream targets promoting epidermal proliferation and differentiation.

II. Signaling networks in epidermal carcinogenesis

Ras activation has emerged as a hallmark feature of a majority of human epidermal cancers, including squamous cell carcinomas (SCC), the second most common malignancy in the United States. In addition to Ras induction, evidence for NF-kB pathway loss-of-function and JNK cascade gain-of-function has also been established in spontaneous human SCCs. In order to study interactions between these dominant signaling cascades, we take the approach of using multiplex serial gene transfer (MSGT) in which alterations in multiple signaling networks can be rapidly achieved in normal cells and tissue. 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-kB blockade or JNK induction in conjunction with Ras activation is sufficient to transform normal human epidermal cells directly into invasive neoplasia. Our current ongoing efforts are directed at 1) exploring mechanisms of JNK signaling in epidermal carcinogenesis, including identification of JNK upstream mediator and downstream targets important in epidermal malignancy, and 2) exploring therapeutic values of blocking JNK-AP1 signaling axis in treating human SCC as well as other diseases.

People Top of Page

Jin, Yingai (Jane), MD.	Research Technician II	684-8037	YJ12@notes.duke.edu
Leshin, Benjamin, BA.	Research Intern Premedical student	684-8037	benleshin@gmail.com
Lutfeali, Shazia	Undergraduate	684-8037	shazia.lutfeali@duke.edu
Ke, Hengning, MD/PhD.	Postdoctoral Associate, Senior	684-8037	keh@niehs.nih.gov (Temporary)
Miliani de Marval, Paula L, PhD.	Postdoctoral Associate	681-1525	paula.milianidemarval@duke.edu

Left to Right

Shazia Lutfeali; Paula L Miliani de Marval, PhD.; Benjamin Leshin, BA.;

Jennifer Zhang, PhD.; Yingai (Jane) Jin, MD.;

Relevant Publications: Top of Page

Adler AS, Sinha S, Tiara, Zhang JY, Segal E and Chang HA. Motif module map reveals enforcement of aging by continual NF-kB activity. (Genes and Development, in press).

*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. 67:3827-34, 2007. (* Corresponding Authors).

Zhang JY, Tao S, Kimmel R and Khavari PA. CDK4 regulation by TNFR1 and JNK is required for NF-kB-mediated epidermal growth control. Journal of Cell Biology 168:561-6, 2005.

Zhang JY, Green CL, Tao S and Khavari PA. RelA opposes epidermal proliferation driven by TNFR1-JNK. Genes & Development 18:17-22, 2004.

Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Kubo Y and Khavari PA. NF-kB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421:639-643, 2003.

Hinata K, Gervin AM, Zhang JY and Khavari PA. Divergent gene regulation and growth effects by NF-kB in epithelial and mesenchymal cells of human skin. Oncogene 22:1955-64. 2003.

Lazarov M, Green CL, Zhang JY, Kubo Y, Dajee M and Khavari PA. Escaping G1 restraints on neoplasia-Cdk4 regulation by Ras and NF-kB. Cell Cycle 2:79-80, 2003.