Yunyan Zhang
Associate Professor in Dermatology
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.
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.
Current Appointments & Affiliations
- Associate Professor in Dermatology, Dermatology, Clinical Science Departments 2013
- Assistant Professor in Pathology, Pathology, Clinical Science Departments 2012
- Member of the Duke Cancer Institute, Duke Cancer Institute, Institutes and Centers 2005
Contact Information
- 200 Trent Dr., Duke Hospital S. Purple Z. Rm 4032, Durham, NC 27710
- Duke Box 3135, Durham, NC 27710
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jennifer.zhang@duke.edu
(919) 684-6794
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