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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes
Andrei L Gartel1, Ksenya Shchors
1Department of Molecular Genetics, M/C 669, 900 S Ashland Avenue, University of Illinois at Chicago, Chicago, IL 60607, USA. agartel@uic.edu
Abstract:
Constitutive expression of the proto-oncogene c-myc results in oncogenic activation and contributes to progression of a wide range of human and animal tumors. Myc executes its multiple activities mostly through transcriptional regulation of the target genes. The special interest of this review is the mechanism of transcriptional repression of cell cycle inhibitors by Myc. Myc suppresses expression of cell cycle/growth arrest genes gas1, p15, p21, p27, and gadd34, -45, and -153. It appears that Myc represses growth arrest gene transcription by at least two distinct mechanisms. One mechanism is limited to the binding of Myc-Max heterodimers to the Inr element in their promoters and inhibition of Miz-1 or other transcriptional activators via the C-terminal domain of c-Myc. This mechanism requires DNA binding of the Myc-Max complex to Inr sequences. The other mechanism is dependent on c-Myc binding to the Sp1 transcription factor via the c-Myc central region and inhibition of Sp1 transcriptional activity. At this time it is not entirely clear which Sp1-containing promoters will be repressed by c-Myc and what other modes of c-Myc transcriptional repression may exist. The ability of c-Myc to repress transcription of growth arrest genes may contribute to its potential to promote proliferation and oncogenesis.
Insights
The proto-oncogene c-myc drives tumor progression by repressing cell cycle inhibitors. This review details how c-myc uses distinct mechanisms to suppress growth arrest genes, promoting cancer cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Constitutive expression of the proto-oncogene c-myc is implicated in oncogenesis and tumor progression.
- c-myc exerts its functions primarily through transcriptional regulation of target genes.
Purpose of the Study:
- This review focuses on the mechanisms by which c-myc transcriptionally represses cell cycle inhibitors.
- Investigate how c-myc suppresses the expression of growth arrest genes, contributing to cancer development.
Main Methods:
- Review of literature on c-myc's role in transcriptional repression.
- Analysis of distinct molecular mechanisms employed by c-myc to inhibit gene expression.
Main Results:
- c-myc represses key cell cycle/growth arrest genes including gas1, p15, p21, p27, and gadd34, -45, -153.
- Two primary repression mechanisms identified: 1) Myc-Max heterodimer binding to Inr elements and inhibiting transcriptional activators, and 2) c-myc interaction with Sp1 transcription factor, inhibiting its activity.
- The precise Sp1-containing promoters targeted by c-myc and potential additional repression modes require further elucidation.
Conclusions:
- c-myc's ability to repress growth arrest genes is a critical factor in promoting cell proliferation and oncogenesis.
- Understanding these repression mechanisms offers insights into cancer development and potential therapeutic targets.
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