Many functions of the Grainyhead-like (Grhl) transcription factors have already been studied in various animal models. So far these studies have been primarily concerned with the roles of such factors in development and wound healing. Now we have new preliminary data indicating that the Grhl factors are potential novel tumor suppressors. We have already established that the Grhl1-deficient mice have increased susceptibility to chemically induced cutaneous tumor development. We have also generated a list of putative targets of GRHL1 regulation, which are known to be involved in cancer. The proposal outlined here aims to further investigate the role of the Grhl1 gene in skin cancer. We plan to characterize the process of tumorigenesis in the Grhl1-null mice in response to chemical carcinogens and UV radiation. We will analyze the proliferation, differentiation and apoptosis in the induced skin of Grhl1-deficient mice and in the Grhl1-null keratinocytes. We will examine the expression of candidate GRHL1 target genes in these contexts and the binding of GRHL1 to its putative target sites. We will profile changes in gene expression during chemically- and UV-induced tumorigenesis in the Grhl1-deficient mice using microarray technology. Our ultimate aim is to unravel the molecular mechanisms underlying the Grhl1 function in skin cancer. The results of this work may thus have medical significance.