Faculty Investigator - Randall J. Urban, M.D.

Randall J. Urban, M.D.
Professor
Internal Medicine, Div. of Endocrinology
email: rurban@utmb.edu

Insulin-like growth factor I (IGF-I) is a growth factor with a variety of biological effects in many different tissues. While much is known regarding cellular mechanisms in the IGF-I signaling pathway through the IGF-I receptor, little is known regarding mechanisms of transcriptional regulation of IGF-I effects on cells.

Our studies identified an IGF-I responsive element in the upstream region of the porcine P450 side chain cleavage gene (P450scc) (1) . This is a 30 base pair region that is GC rich, binds the transcription factor Sp1, and is active with a heterologous promoter in transient transfection experiments in MCF-7 breast cancer cells (2) . TNF-a will inhibit IGF-I transcriptional effects through the response element indicating multiple cellular pathways interact on the element (3) . Additional analysis identified a second protein binding to the response element, PTB-associated splicing factor (PSF) (4) . PSF is a complex protein that contains multiple prolines and glutamines and is involved in formation and function of the spliceosome. Transient transfection studies show that Sp1 is primarily responsible for stimulation of the response element by IGF-I while PSF inhibits function of the response element. Studies are currently investigating the interactions of the transcription factors binding to this response element and the PKC signaling pathway. Interactions of Sp1, PSF, and the PKC pathway may be important in the pathogenesis of specific cancers.

Urban RJ, Shupnik MA, Bodenburg YH. Insulin-like growth factor I increases expression of porcine P-450 cholesterol side-chain cleavage gene through a GC-rich domain. J Biol Chem 1994; 269(41):25761-25769.

Urban RJ, Bodenburg YH. Transcriptional activation of the porcine P-450 11A insulin-like growth factor response element in MCF-7 breast cancer cells. J Biol Chem 1996; 271:31695-31698.

Urban RJ, Nagamani M, Bodenburg YH. Tumor necrosis factor alpha inhibits transcriptional activity of the porcine P-450 11A insulin-like growth factor response element. J Biol Chem 1996; 271:31699-31703.

Urban RJ, Bodenburg YH, Kurosky A, Wood TG, Gasic S. PTB-associated splicing factor is a negative regulator of transcriptional activity of the porcine P450scc insulin-like growth factor response element. Mol Endocrinol 2000; 14:774-782.

Last Revised: Jan. 2004