REGULATION OF ONCOGENIC ACTIVITY BY DBL FAMILY PROTEINS

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DESCRIPTION: (dapted from applicant abstract) The Dbl-related oncogenes encode a large, structurally related family of growth regulatory proteins originally identified as transforming or invasion inducing(e.g., Dbs, Lfc and Lsc). Consequently , it is widely believed that the deregulated expression of Dbl family proteins can contribute to the aberrant growth, invasiveness and metastatic potential of tumor cells. Dbl proteins are activators of Rho family GTPases, and their transforming properties has been attributed to their aberrant upregulation of Rho activity. The large number of Dbl proteins that have been recently described, as well as the increasing number of their GPTase targets, is ample evidence of the important regulatory roles that these proteins will play in a multitude of biological processes. However, much remains to be learned about the mechanisms through which Dbl proteins mediate their biological activities, and about the contributions of these activities to human malignancies. Three specific aims are proposed to directly address these two important issues. First, although several studies have implicated the Rho proteins as the immediate targets of the Dbl protein transforming activity, there have been limited structure-based analyses done on the role of the catalytic activity in Dbl protein transformation. In specific Aim 1 the author will determine if Lfc transformation is dependent on its ability to bind, and activate RhoA. This approach will also generate valuable reagents that can be used to determine if Lfc is the critical link between extracellular signaling pathways and RhoA activation. Second, although the applicant has recently shown that Dbl proteins share a common ability to activate multiple signaling pathways (e.g., JNK, p38, SRF and NFKB), the contribution of any of these pathways to Dbl-mediated transformation, are unknown. In Specific Aim 2 he directly assess the contribution of JNK, p38 and NFKB to the transforming activity of the Dbs protein. Finally, transformation studies on Dbl protein have relied heavily on fibroblast cell systems. As a consequence the contribution of Dbl proteins to human carcinogenesis is still not known. In Specific Aim 3 the role of Lfc, Lsc and Dbs proteins in mediating the differentiation and invasive potential of the T47D human breast epithelial cell line will be examined. Based on his preliminary data, he anticipates that T47D will be an important system to address the contribution of the Dbl family proteins to epithelial cell transformation. Taken together, the investigator feels that these studies will contribute significantly to understand the mechanisms through which Dbl proteins contribute to aberrant cell growth and the development of human cancers.