Characterization of transforming growth factor-alpha promoter regulation and its role in the malignant progression of colon carcinoma

• Main Author: Awwad, Rana Ali
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-1999
• Subjects: Cellular biology; Molecular biology; Oncology
• ISBN: 9780599251779; 0599251778

We have demonstrated that regulation of TGFα expression is dependent on the interaction of two regulatory elements, a repressor and an activator, within the TGFα promoter. These elements regulate TGFα expression in response to exogenous EGF/TGFα as well as endogenous TGFα. Furthermore, the activity of the trans-acting factors that bind to these elements is modulated by exogenous EGF/TGFα treatment and endogenous TGFα levels. Thus, the activity of these trans-acting factors is indicative of the level of TGFα autocrine activity within a certain phenotype. We further demonstrate that the underlying mechanism for malignant progression in vivo is the increased activity, and perhaps expression, of these trans-acting elements such that TGFα autocrine levels are sustained at high levels during growth arrest. The alterations in TGFα autocrine activity eventually leads to altered regulation of the cell cycle. Epidermal growth factor receptor involvement is suggested, and is very likely since enhancing the TGFα autocrine loop through the increased levels of endogenous TGFα or by exogenous EGF/TGFα can enhance the binding of these factors. The sequence of the identified EGF/TGFα regulatory element is unique which indicates the novelty of the trans-acting factors that bind to it. Isolation and subsequent characterization of these factors will provide new insights into colon cancer therapy specifically and other cancer types in general.