How appropriate regulation of gene expression is achieved remains one of the principal challenges of modern biology. The current focus of the lab is on transcriptional mechanisms which control expression of fut7, which encodes a glycosyltransferase called FucT-VII. This enzyme is critical for biosynthesis of carbohydrate ligands for a family of molecules called selectins, which control leukocyte traffic. Although a number of glycosyltransferases are involved in selectin ligand formation in various cells, FucT-VII is the only one which is critical for all selectin ligands and the only one which exhibits a highly restricted pattern of expression. In particular, FucT-VII is expressed in hematopoietic cells and a subset of endothelial cells called high endothelial venules (HEV), and is absent from all other cells. Further, FucT-VII is expressed constitutively in myeloid cells such as neutrophils but induciblyin response to specific cytokines in lymphoid cells such as CD4+ T cells. How this complex and unique pattern of gene expression is achieved is not well understood.
We are presently focused most closely on two parallel questions: what are the cis-acting elements within the fut7 locus which govern fut7 gene expression? And how do certain transcription factors that we have identified actually control gene expression? Explorations into these questions should yield insight into several important questions in genetics and gene regulation, including the mechanisms by which various classes of cis-acting elements control gene expression as well as mechanisms utilized by distinct types of transcription factors to govern gene expression.
Selected Publications:
Wagers AJ, Waters CM, Stoolman LM, Kansas GS. IL-12 and IL-4 control T cell adhesion to endothelial selectins through opposite effects on FucT-VII gene expression. J Exp Med, 1998, 188, 2225.
Wagers AJ, Kansas GS. Potent induction of FucT-VII by TGF- β 1 through a p38 MAP kinase-dependent pathway. J Immunol, 2000, 165: 5011.
White SJ, Underhill GH, Kaplan MH, Kansas GS. Cutting Edge: Differential requirements for Stat4 in expression of glycosyltransferases responsible for selectin ligand formation in Th1 cells. J Immunol, 2001, 167: 628.
Barry SM, Zisoulis DG, Neal JW, Clipstone NA, Kansas GS. Induction of FucT-VII by the Ras/MAP Kinase cascade in Jurkat T cells. Blood 2003, 102: 1771.
Zisoulis, DG, Kansas GS. H-Ras and PI3K cooperate to induce FucT-VII expression in Jurkat T cells. J Biol Chem, 2004, 279: 39495.
Underhill GH, Zisoulis D, Kolli KP, Ellies LG, Marth, JD, Kansas GS. A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells. Blood, 2005, 106: 3867.
Fornek JL, Tygrett L, Waldschmidt TJ, Poli V, Rickert RC, Kansas GS. Critical Role for Stat3 in T-Dependent Terminal Differentiation of IgG B cells. Blood, 2006, 107: 1085.
