(Adapted from abstract) Smads are newly identified proteins that mediate intracellular signaling for the transforming growth factor (TGF-beta) superfamily. Additionally, mutations/deletions in smad genes have been observed in many human cancers, suggesting that smads may function as tumor suppressors. Although biochemical studies have brought about remarkable achievements in the elucidation of the intracellular signaling mediated by smads, the physiological functions of smads remain to be determined. Since the TGF-beta superfamily is pivotal in maintenance of epidermal homeostasis, and plays important roles in skin carcinogenesis, the epidermis will provide a unique tissue to study smad functions. In this proposal, Dr. Wang will generate inducible and epidermal-specific knockout mice for individual smad isoforms. These knockout mice will provide in vivo models that circumvent the embryonic lethality resulting from the germline knockout of individual smad genes. The applicant will utilize these models to study the functions of smads in epidermal proliferation, differentiation, angiogenesis and wound-healing. She will also perform chemical carcinogenesis experiments on these mice to determine the stage-specific role of smads in skin carcinogenesis (initiation, promotion and malignant progression). The mechanisms involved in cell cycle progression, genetic instability, apoptosis and angiogenesis will be further analyzed in smad knockout tumors. The epidermis and tumors generated from these knockout mice will be used to identify the transcriptional targets of smad genes in epidermal proliferation, differentiation and carcinogenesis. The proposed studies utilizing these animal models will address unsolved questions regarding the roles and mechanisms of TGF-beta signaling in epidermal proliferation, differentiation and cancer. In addition, these animal models will identify functions of smads independent of TGF signaling. These studies will also determine whether smads can be major targets of therapeutic approaches for skin diseases and cancer, and animal models generated in this proposal can be used to test these approaches in the future.