David C. Seldin, M.D., Ph.D.
Professor of Medicine and Microbiology
Director, Graduate Program in Molecular Medicine
My laboratory uses transgenic and knockout mouse models to complement biochemical and cell biological studies of the role of serine-threonine kinases in cellular growth control. Serine and threonine phosphorylation of proteins is much more common than tyrosine phosphorylation, but less well understood. We study a kinase, protein kinase CK2 (casein kinase II), that controls the rate of degradation of critical cellular regulators in the NF-κB (1) and Wnt pathways (2). CK2 itself can behave as an oncogene when expressed in a dysregulated fashion in cells or in the mammary gland (3). The Wnt pathway is also regulated by GSK3β, and these kinases together appear to regulate epithelial/mesenchymal fate decisions of cancer cells, and invasion and metastasis. In addition to characterizing pathological situations in which CK2 dysregulation leads to cancer, we are using gene targeting technology to characterize the essential development roles of the isoforms of CK2 (4). A second area of research in the laboratory is the disease systemic (AL) amyloidosis, in which clonal immunoglobulin light chains form fibrillar deposits in tissues leading to organ failure and death. We are cloning, sequencing and expressing patient amyloidogenic light chains to develop animal models for the pathogenesis and treatment of this clonal plasma cell disease (5).
1. Eddy, S. F., S. Guo, E. G. Demicco, R. Romieu-Mourez, E. Landesman-Bollag, D. C. Seldin, and G. E. Sonenshein. 2005. Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. Cancer Res 65:11375-11383.
2. Seldin, D. C., E. Landesman-Bollag, M. Farago, N. Currier, D. Lou, and I. Dominguez. 2005. CK2 as a positive regulator of Wnt signalling and tumourigenesis. Mol Cell Biochem 274:63-67.
3. Landesman-Bollag, E., R. Romieu-Mourez, D. H. Song, G. E. Sonenshein, R. D. Cardiff, and D. C. Seldin. 2001. Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20:3247-3257.
4. Xu, X., P. A. Toselli, L. D. Russell, and D. C. Seldin. 1999. Globozoospermia in mice lacking the casein kinase II alpha’ catalytic subunit. Nat Genet 23:118-121.
5. Ward JE, Brenner DA, Eberhard J, Liao R, Connors LH, O’Hara C, Seldin DC. In vitro and in vivo mouse models for AL amyloidosis. In Amyloid and Amyloidosis, Ed by G Grateau, RA Kyle, M Skinner, CRC Press, Boca Raton, pp64-66, 2005.
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