SUNY Downstate Health Sciences University
Department of Cell Biology
William Chirico, PhD
Director, Molecular and Cellular Biology Program
School of Graduate Studies
Tel: (718) 270-1308 • Fax: (718) 270-3732
Biogenesis and Mechanism of Angiogenic Factors:
Angiogenesis is essential for the development, growth, and maintenance of cardiovascular tissue and for tumor growth. Cells secrete a variety of factors that promote vascularization. For example, vascular endothelial growth factor (VEGF) stimulates vasculogenesis, the growth of new blood vessels, and basic fibroblast growth factor (bFGF or FGF2) stimulates angiogenesis, the growth of existing blood vessels. Other factors, such as angiostatin and endostatin, inhibit angiogenesis. Together these and other factors orchestrate the development of blood vessel networks.
Our laboratory is focused on two aspects of angiogenesis. First, we are examining the mechanism by which FGF2 directly regulates cell growth in the nucleolus. Second, we are elucidating the biogenesis of a key enzyme in the production of angiostatin.
FGF2 is a potent angiogenic factor. We recently deciphered the signals controlling its nuclear and nucleolar localization. Using FGF2 as bait, we identified several specific binding proteins located in the nucleus including nucleolin, histone H1, ribosomal protein P0, and the upstream binding factor (UBF). UBF plays a critical role in cell growth by regulating rRNA transcription. We demonstrated that FGF2 directly regulates rRNA transcription by interacting with UBF. Thus, FGF2 regulates cell growth extracellularly through cell surface receptors and intracellularly in the nucleolus through components of the rRNA transcription machinery.
Angiostatin, an angiogenesis inhibitor, is produced extracellularly by the coordinated action of an ensemble of enzymes, including phosphoglycerate kinase (PGK1). Although PGK1 is a key glycolytic enzyme, it can be secreted from certain cells. PGK1 lacks features common to many secreted proteins, such as N-terminal signal sequence and glycosylation sites. We have recently shown that export of PGK1 is stimulated by brefeldin A, an inhibitor of the classical secretory pathway. This result suggests that PGK1 is exported through a nonclassical pathway. One of our long-term goals is to elucidate the nonclassical secretory pathway of PGK1 and its role in angiogenesis.
We believe that our studies will provide new insight into the regulation of angiogenesis and aid the development of new treatments for cardiovascular disease and cancer.
- Sheng, Z., Liang, Y., Lin, C-Y., Comai, L., and W.J. Chirico, Direct regulation of rRNA transcription by fibroblast growth factor 2. Mol. Cell. Biol., 2005. 25(21):9419-26.
- Sheng, Z., J.A. Lewis, and W.J. Chirico, Nuclear and nucleolar localization of 18-kDa fibroblast growth factor-2 is controlled by C-terminal signals. J Biol Chem, 2004. 279(38):40153-60.
- Sheng, Z., S.B. Chang, and W.J. Chirico, Expression and purification of a biologically active basic fibroblast growth factor fusion protein. Protein Expr Purif, 2003. 27(2):267-71.
- Ngosuwan, J., N. M. Wang, K. L. Fung, and W. J. Chirico, Roles of cytosolic Hsp70 and Hsp40 molecular chaperones in post-translational translocation of presecretory proteins into the endoplasmic reticulum. J Biol Chem 2002. 278:7034-42.