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Regulation of the insulin-like growth factor-I receptor gene by oncogenes and antioncogenes: implications in human
H Werner1, M Shalita-Chesner, S Abramovitch
1Department of Clinical Biochemistry, Tel Aviv University, Tel Aviv, 69978, Israel. hwerner@post.tau.ac.il
Abstract:
The insulin-like growth factor-I receptor (IGF-I-R) has a central role in normal cellular proliferation as well as in transformation processes. Transcription of the IGF-I receptor gene is controlled by a number of tumor suppressors, including WT1, p53, and BRCA1. It has been demonstrated that, in their wild-type form, these transcription factors can suppress the activity of the IGF-I-R promoter, with ensuing reduction in the levels of cell-surface IGF binding. On the other hand, a number of oncogenes, including mutant p53 and c-myb, and the fusion protein EWS-WT1 significantly stimulate promoter activity. Interactions between stimulatory and inhibitory transcription factors may determine the level of expression of the IGF-I-R gene and, consequently, the proliferative status of the cell.
Insights
Tumor suppressors like WT1 and p53 inhibit insulin-like growth factor-I receptor (IGF-I-R) gene activity, while oncogenes stimulate it. This balance regulates cell proliferation and transformation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The insulin-like growth factor-I receptor (IGF-I-R) is crucial for cell growth and cancer development.
- Tumor suppressor genes (e.g., WT1, p53, BRCA1) and oncogenes influence IGF-I-R gene expression.
- Dysregulation of IGF-I-R signaling is implicated in various cancers.
Purpose of the Study:
- To investigate the regulatory mechanisms controlling IGF-I receptor gene transcription.
- To elucidate the roles of specific tumor suppressors and oncogenes in modulating IGF-I-R promoter activity.
- To understand how the interplay between transcription factors impacts cellular proliferation.
Main Methods:
- Analysis of IGF-I receptor gene promoter activity.
- Investigation of transcription factor binding and function.
- Assessment of cell-surface IGF binding levels.
Main Results:
- Wild-type tumor suppressors (WT1, p53, BRCA1) suppress IGF-I-R promoter activity.
- Oncogenes (mutant p53, c-myb) and EWS-WT1 fusion protein stimulate IGF-I-R promoter activity.
- Differential regulation by transcription factors affects IGF-I-R expression and cell proliferation.
Conclusions:
- The expression of the IGF-I receptor is tightly controlled by a balance of stimulatory and inhibitory transcription factors.
- Understanding these regulatory interactions is key to comprehending cell proliferation and transformation processes.
- Targeting IGF-I-R signaling pathways holds potential for cancer therapy.