Faculty

Assistant Adjunct Professor of Pharmacology

email: tseasholtz@ucsd.edu

Key Words: Cell Proliferation and Migration in Vascular Disease and Cancer; Small G Proteins, Nitric Oxide Signaling.

I am interested in the signaling pathways from G protein coupled receptors to cellular proliferation and migration. Cell proliferation and migration, while normal physiological processes in development and wound repair, are dysregulated in pathologies such as vascular disease. Specifically, in hypertension, blood vessels not only respond with enhanced contractile responses, but also with an enhanced ability to proliferate and migrate to form vessel occlusions. Our work examines alterations in normal vascular growth signals in hypertension, which predispose to atheroslerosis, restenosis and kidney failure. We have found that the small G protein Rho is required for vascular proliferation and migration and that Rho-dependent vascular growth is enhanced in hypertension. We have additionally discovered that Rho activity is upregulated in vessels and vascular smooth muscle cells from genetically hypertensive rats and nitric oxide (NO)-deficient hypertensive rats. Enhanced vascular reactivity in hypertension is also characterized by endothelial cell defects resulting in reduced nitric oxide (NO) signaling. NO release from endothelial cells acts as a physiological antagonist of Rho signaling by inhibiting vascular contraction, proliferation and migration. Our findings suggest that vascular smooth muscle cells also produce NO and that constitutive release of smooth muscle-derived NO provides tonic inhibition of Rho activation. We are currently investigating the interaction of the NO-Rho pathways as they relate to vascular growth in response to not only GPCR stimulation, but also mechanical stretch. A new area of investigation being conducted in our lab examines dysregulation of cell growth and migration in the development of invasive human cancer cells.

Selected Publications:

Seasholtz, T.M.*; Johnson, E.N.*; Waheed, A.A.; Kreutz, B.; Suzuki, N.; Kozasa, T.; Jones, T.L.Z.; Brown, J.H.; Druey, K.M.: RGS16 Inhibits Signaling through the G face="Symbol">a13-Rho Axis. Nature Cell Biology. In Press.

* These authors contributed equally to this work.

Seasholtz, T. M.: Commentary: The RHOad Less Traveled: The Myosin Phosphorylation-Independent Path from Rho Kinase to Cell Contraction. American Journal of Physiology, Cell Physiology. 284(3):C596-C598, 2003.

Ostrom, R.S.; Liu, X.; Gregorian, C.; Seasholtz, T.M.; Insel, P.A.: Compartmentation of Adenylyl Cyclase Isoform Expression and Receptor Coupling in Aortic Smooth Muscle Cells. Molecular Pharmacology. 62(5):983-992, 2002.

Gudi, T.; Chen J.C.; Casteel, D.E.; Seasholtz, T.M.; Boss, G.R.; Pilz, R.B.: cGMP-Dependent Protein Kinase Inhibits Serum Response Element-Dependent Transcription by Inhibiting Rho Activation and Functions. Journal of Biological Chemistry. 277(40):37382-37393, 2002.

Seasholtz, T.M.; Zhang, T.; Morissette, M.R.; Howes, A.L.; Yang, A.H.; Brown, J.H.: Increased Expression and Activity of RhoA is Associated with Increased DNA Synthesis and Reduced p27^Kip1 Expression in the Vasculature of Hypertensive Rats. Circulation Research. 89:488-495, 2001.

Seasholtz, T.M.; Cai, G.; Wang, H.-Y.; Friedman, E.: Effects of Ischemia-Reperfusion on Vascular Contractility and face="Symbol">a1 Adrenergic Receptor Signaling in the Rat Tail Artery. Journal of Applied Physiology. 91:1004-1010, 2001.

Sagi, S.M.; Seasholtz, T.M.; Kobiashvili, M.; Wilson, B.A.; Toksoz, D.; Brown, J.H.: Physical and Functional Interactions of G face="Symbol">a_q with the Rho and its Exchange Factors. Journal of Biological Chemistry. 276:15445-15452, 2001.

Sah, V.P.; Seasholtz, T.M.; Sagi, S.A.; Brown, J.H.: The Role of Rho in G Protein-Coupled Receptor Signal Transduction. Annual Review of Pharmacology and Toxicology. 40:459-489, 2000.