My long-term interest and the objective of this proposal are to better understand the pathogenesis of epithelial neoplasms, such as basal cell carcinomas (BCCs). I am completing training in anatomic pathology while serving as an autopsy fellow at Stanford University Medical Center. I propose to conduct a 5-year, mentored, research experience within the laboratory of Dr. Tony Oro to enhance my research skills in cutaneous tumor biology. This scientific training, combined with my continued and limited autopsy service work, will establish an exceptional foundation for my future independent research program. Basal cell carcinomas are one of the most common cancers worldwide and induction of Sonic hedgehog (Shh) target genes are critical to their pathogenesis. To isolate and characterize key Shh target genes involved in BCC formation, the Oro laboratory devised a model for human BCCs which formed the basis of a microarray screen for BCC-enriched genes (BEG's). One recently isolated gene, BEG4, is a Shh target gene and its overexpression in cultured, human keratinocytes leads to dramatic increases in keratinocyte growth. BEG4 is represented by a single, 5.5 kb transcript and encodes a novel, proline-rich protein with similarity to the Wiskott-Aldrich Syndrome protein (WASp). Together, these findings suggest that BEG4 influences Shh-dependent tumor growth by coordinating and distributing growth factor signals to the actin cytoskeleton. This proposal aims to understand BEG4's role as a Shh pathway target gene and a mediator of epithelial growth by: l) characterizing BEG4 expression in skin and other tissues where Shh target genes are induced, 2) determining the importance of BEG4 function in vivo through the analysis of BEG4lmockout mice, and 3) determining the consequences of BEG4 overexpression in human and mouse skin. The proposed research fellowship will yield new insights into the pathogenesis of BCCs and other Shh pathway-related malignancies and may lead to the identification of new targets for prevention and therapy.
|Callahan, Christopher A; Ofstad, Tyler; Horng, Lily et al. (2004) MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev 18:2724-9|