Professor
Depts. Anatomy & Cell Biology and Pharmacology
Tufts University School of Medicine
136 Harrison Avenue
Boston, MA 02111
Phone: 617-636-0303
Email: John.Castellot@tufts.edu

Castellot Laboratory: http://www.tufts.edu/sackler/cmdb/castellot-lab.htm

Research Interests:

Nearly half of the estimated two million deaths recorded in the U.S. each year are attributable to diseases of the heart and blood vesels. Most of these deaths are due to atherosclerosis and its ensuing complications, which include hypertension, myocardial infarction, and gangrene. Aberrant vascular smooth muscle cell proliferation is the hallmark of both atherosclerosis and restenosis seen after vascular surgery. Heparin and heparan sulfates have been shown to inhibit smooth muscle cell proliferation in cell culture and in animal models. Although the precise mechanism of action of the antiproliferative effect of heparin is not yet understood, studies in Dr. Castellot's laboratory focus on: 1) binding of heparin to specific cell surface receptors and its subsequent internalization; 2) effects on cell cycle control machinery; 2) alteration of mitogenic signaling pathways; and 4) regulation of gene expression, especially genes that encode proteins required for proliferation. Recent studies have identified several key signal transduction molecules that are inhibited by heparin, including MAPK and calcium/calmodulin activated mitogen kinase II. He has also discovered a novel growth-arrest gene that is specifically induced by heparin in smooth muscle cells. The goal of the Castellot laboratory is to elucidate the mechanisms regulating proliferation of smooth muscle cells (SMC), using a concerted biochemical, molecular, and cell biological approach. Hyperproliferation of vascular SMC can lead to a wide variety of pathologies, including hypertension and atherosclerosis. SMC hyperproliferation is responsible for the 20-30% failure rates following vascular procedures such as angioplasty and coronary artery bypass grafts. Understanding the role played by these heparin-modulated genes and signaling kinases in smooth muscle cell proliferation is a major focus of the laboratory.

Recent Publications:

Aprahamian T, Rifkin I, Bonegio R, Hugel B, Freyssinet JM, Sato K, Castellot JJ, Jr. and Walsh K. Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med 2004;199:1121-1131.

Mason HR, Lake AC, Wubben JE, Nowak RA and Castellot JJ, Jr. The growth arrest-specific gene CCN5 is deficient in human leiomyomas and inhibits the proliferation and motility of cultured human uterine smooth muscle cells. Mol Hum Reprod 2004;10:181-187.

Mason HR, Grove-Strawser D, Rubin BS, Nowak RA and Castellot JJ, Jr. Estrogen induces CCN5 expression in the rat uterus in vivo. Endocrinology 2004;145:976-982.

Lake AC and Castellot JJ, Jr. CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells. Cell Commun Signal 2003;1:5.

Mason HR, Grove-Strawser D, Rubin BS, Nowak RA and Castellot JJ, Jr. Estrogen induces CCN5 expression in the rat uterus in vivo. Endocrinology 2004;145:976-982.

Anastase-Ravion S, Blondin C, Cholley B, Haeffner-Cavaillon N, Castellot JJ and Letourneur D. Heparin inhibits lipopolysaccharide (LPS) binding to leukocytes and LPS-induced cytokine production. J Biomed Mater Res A 2003;66:376-384.

Mason HR, Nowak RA, Morton CC and Castellot JJ, Jr. Heparin inhibits the motility and proliferation of human myometrial and leiomyoma smooth muscle cells. Am J Pathol 2003;162:1895-1904.

Lake AC, Bialik A, Walsh K and Castellot JJ, Jr. CCN5 is a growth arrest-specific gene that regulates smooth muscle cell proliferation and motility. Am J Pathol 2003;162:219-231.