Epidermis undergoes continuous self-renewal through a tight balance of cell proliferation, differentiation and cell death. This balance is regulated by both epidermal cell-intrinsic processes and paracrine effects from dermal cells, including fibroblasts and lymphocytes. Among a complex array of signaling molecules and transcription factors, the IKK/NF-: B and JNK/AP-1 signaling cascades have been implicated as dominant regulators in mediating epidermal cell-intrinsic processes. NF-: B controls epidermal growth, while AP-1 induction via JNK is responsible for the epidermal hyperplasia and neoplasia associated with NF-: B blockade. However, there are functional diversities and even antagonisms among AP-1 subunits. Specifically, although both JunB and c-Jun are involved in mediating epidermal differentiation markers, JunB inhibits epidermal cell growth and induces cell senescence;whereas c-Jun promotes epidermal growth and neoplasia. Moreover, epidermal-specific deletion of JunB alone or along with c-Jun, but not c-Jun alone, in mice leads to an inflammatory skin phenotype with resemblance to human arthritic and psoriatic diseases. These findings underscore important roles for JunB and c-Jun in epidermal well-being and pathogenesis, and suggest that they are functionally antagonistic and redundant in mediating epidermal cell growth and differentiation, respectively. The first goal of this proposal is to determine the molecular mechanisms of Jun proteins in mediating epidermal cell-intrinsic processes. To do this, we will perform systemic structure-functional studies to define the functional specificity of JunB and c-Jun sub-domains in epidermal growth and differentiation. We will also determine the nature of the antagonism or synergism between JunB and c- Jun, and identify their downstream target genes by genome-wide gene expression analysis. The second goal is to determine how JunB and c-Jun contribute to epidermal tumorigenesis. To do this, we will use the recently established human squamous cell carcinoma models to examine gain- or loss-of-function effects of JunB and c-Jun, as well as their downstream target, p16, on epidermal tumor growth, maintenance and regression. This effort is based on the premise that characterizing the molecular mechanisms governing the functional specificity of JunB and c-Jun will provide new insights into both basic epithelial biology and better defined therapeutic targets.
Abnormalities of epidermal growth or differentiation account for many diseases affecting a large proportion of the U.S. population. Among these disorders are atopic dermatitis, psoriasis, squamous cell carcinoma, basal cell carcinoma and chronic wounds. The efforts of this proposal are designed to characterize the genetic regulatory mechanisms governing epidermal homeostasis and neoplastic pathogenesis, and therefore provide meaningful insights to better defined therapeutic targets for skin disorders as well as other types of diseases.
|Wang, Y; Zhang, G; Jin, J et al. (2017) MALT1 promotes melanoma progression through JNK/c-Jun signaling. Oncogenesis 6:e365|
|Zhang, Xiaoling; Luo, Suju; Wu, Joseph et al. (2017) KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage. J Invest Dermatol 137:475-483|
|Jin, Yingai Jane; Wang, Sally; Cho, Joshua et al. (2016) Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors. JCI Insight 1:|
|Zhang, Xiaoling; Jin, Jane Y; Wu, Joseph et al. (2015) RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-?B-dependent inflammation. J Invest Dermatol 135:1016-1024|
|Ke, Hengning; Augustine, Christina K; Gandham, Vineela D et al. (2013) CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and ?1-integrin signaling pathways. J Invest Dermatol 133:221-9|
|Gandham, V D; Maddala, R L; Rao, V et al. (2013) Effects of Y27632 on keratinocyte procurement and wound healing. Clin Exp Dermatol 38:782-6|
|Zhang, Jennifer Y; Selim, Maria Angelica (2012) The role of the c-Jun N-terminal Kinase signaling pathway in skin cancer. Am J Cancer Res 2:691-8|
|Miliani de Marval, Paula; Lutfeali, Shazia; Jin, Jane Y et al. (2011) CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels. Cancer Prev Res (Phila) 4:851-9|
|Jin, Jane Y; Ke, Hengning; Hall, Russell P et al. (2011) c-Jun promotes whereas JunB inhibits epidermal neoplasia. J Invest Dermatol 131:1149-58|