Joseph Baldassare, Ph.D.
Pharmacological and Physiological Science
MIT and University of Pittsburgh, 1971
The laboratory is currently examining by both molecular biological and biochemical approaches the importance of mitogenic signaling cascades in regulating proliferation. Mutations that effect these cascades are known to be oncogenic and, therefore, result in unregulated growth and tumors. A central question is why is a signaling pathway mitogenic when activated by growth factors but the same pathway not when activated by other stimuli? This question is of fundamental importance for understanding the molecular basis of many cancers. In the past year we have demonstrated that one of these pathways (MAP Kinase) regulates expression of cyclin D, a major cell cycle G1 phase regulatory protein. The laboratory has also found that RhoA, a small GTP-binding protein, is important for the degradation of the tumor suppressor p27Kip protein. Both these pathways were shown to be required for mitogenesis. We also found that sustained activation of the MAP kinase pathway is necessary for growth, and correlates with the ability of mutations in this pathway to result in transformation. Several ongoing projects are: 1) the importance of sustained activation for regulation of retinoblastoma protein, a tumor suppressor, regulation of cell cycle control; 2) the process by which MAP kinase is targeted to the nucleus where it subsequently stimulates expression of cyclin D; and 3) the mechanism by which Rho A controls the loss of p27Kip.
A second major focus of the laboratory is directed at understanding the specificity in G-protein coupled receptors. Why does activation of a specific receptor result in growth in one cell type and not another? To address this question we have generated several stable cell lines in which specific GTP- binding protein subunits have been ablated by expression of antisense mRNAs. Ablation of Go? resulted in transformation whereas stable cells lines with reduced levels of Gq? growth arrested.
- Understanding the mechanism involved in the transformed phenotype in the Go? ablated cells;
- Characterization of mitogenic G-protein signaling pathways, and the specific GTP-binding proteins that activate these pathways.
Weber JD, Hu W, Raben DM, Jefcoat S, and Baldassare JJ (1997) Ras-stimulated ERK and RhoA activities coordinate PDGF-induced G1 progression through the independent regulation of cyclin D1 and p27Kip1. J Biological Chem 272:32966-71.
Padfield PJ, Elliott, AC, and Baldassare JJ (1998) Adenovirus-mediated gene expression in isolated rat pancreatic acini and individual pancreatic acinar cells. European Journal of Physiology 436:782-87.
Mcmurdo L, Stephenson AH, Baldassare JJ, Sprague RS, and Lonigro AJ (1998) Biosynthesis of sulfidopeptide leukotrienes via the transfer of leukotriene A(4) from polymorphonuclear cells to bovine retinal pericytes. Journal of Pharmacology & Experimental Therapeutics 285(3):1255-1259.
Hu W, Bellone CJ, and Baldassare JJ. RhoA stimulates "p27Kip degradation through its regulation of cyclin E/CDK2 activity. Accepted J. of Biological Chemistry.
Baldassare, JJ, Bi Y, and Bellone CJ. The role of p38 MAP kinase in IL-1b transcription. Accepted Journal of Immunology.
Cheng J, Baldassare JJ, and Raben DM Dual coupling of the a-thrombin receptor to signal transduction pathways involving phosphatidylinositol and phosphatidylcholine metabolism. Accepted Biochemical Journal.
Fisher GJ, Weber JD, Raben DM, and Baldassare JJ. Growth factor-induced nuclear localization precedes activation of nuclear ERK-1. Accepted J Biological Chemistry.
Gardner A, Raben DM, Baldassare JJ . Thrombin inhibits extracellular signal-regulated kinase by two independent pathways, one pathway regulated by Gq the other pathway. Submitted to Biochemical Journal.