Paul J. Higgins, PhD

Cell shape, proliferation and differentiation programs are regulated largely by complex interactions between growth factors and elements of the extracellular matrix. Molecular genetic studies in this laboratory identified proteins encoded by the mammalian p52^PAI-1 gene family as key elements in the regulation of cell shape, motility, growth control and tissue invasion. Expression of the p52^PAI-1 genes is controlled in both proliferation- and differentiation-dependent fashions by specific growth factors via Src/MAP kinase/rho-mediated signal transduction pathways. A unique pattern of cell cycle-related p52^PAI-1 gene expression control has been defined. Growth factors of the TGF-ß and EGF families independently trans-activate the p52^PAI-1 gene by means of distinct signaling pathways that utilize stimulus-specific transcriptional control mechanisms. The p52^PAI-1 gene is regulated in a growth state-dependent fashion by the MYC/SMAD/USF/ TFE3 family of transcriptional activators that recognize specific promoter target sequences (E box motifs) to effect gene silencing or inducible expression. p52^PAI-1 transcription in normal cells is relatively low but rapidly induced in emergency conditions such as tissue injury and wound repair under conditions necessitating cell growth, migration and extracellular matrix remodeling. In human cancers, p52^PAI-1 functions as a tumor metastasis/pro-invasive gene and is a critical element in disease progression. Studies in PAI-1 null mice indicate that PAI-1 expression is required for normal as well as pathologic angiogenesis, tumor invasion and vascular network stability. Current investigations in the laboratory bridge two major research themes (vascular biology/angiogenesis and tumor growth/ metastasis) with an emphasis on p52^PAI-1 involvement and development of molecular genetic therapies for vascular and neoplastic diseases. Present work focuses on analysis of the p52^PAI-1 signal transduction pathway, clarifying molecular mechanisms underlying growth state-associated transcriptional control, definition of gene structure, and elucidating the role of p52PAI-1 in cell growth regulation and tumor angiogenesis.