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Negative regulation of human c-fos expression by the retinoblastoma gene product
P D Robbins1, J M Horowitz, R C Mulligan
1Whitehead Institute for Biomedical Research, Nine, Cambridge, Massachusetts 02142.
Abstract:
Inactivation of the retinoblastoma susceptibility gene (RB-1) has been associated with the aetiology of many types of human cancers, leading to the classification of RB-1 as an anti-oncogene or tumour suppressor gene. Given that the protein product of RB-1 (Rb) has a nuclear localization and DNA-binding activity in vitro, it is possible that Rb regulates transcription of certain genes. The promoter of the c-fos gene might be a target for regulation by Rb, because both v-fos and RB-1 are associated with the induction of osteosarcomas in mice and humans, respectively. Also, fos expression is thought to be required for quiescent cells to enter the cell cycle, making the fos promoter an attractive target for suppressors of cell growth. Here we report that Rb can repress c-fos expression and AP-1 transcriptional activity in both serum-induced and cycling 3T3 cells. We have mapped a cis-acting element in the human c-fos promoter that can confer repression by Rb to a heterologous promoter. We have the termed the cis-acting sequence regulated by Rb the retinoblastoma control element.
Insights
The retinoblastoma protein (Rb) represses c-fos gene expression and AP-1 activity. Researchers identified a specific DNA sequence, the retinoblastoma control element, responsible for this repression in the c-fos promoter.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Gene Regulation
Background:
- The retinoblastoma susceptibility gene (RB-1) functions as a tumor suppressor, and its inactivation is linked to various human cancers.
- The RB-1 protein product (Rb) exhibits nuclear localization and DNA-binding capabilities, suggesting a role in transcriptional regulation.
Purpose of the Study:
- To investigate whether the Rb protein regulates the transcription of the c-fos gene.
- To identify the specific regulatory elements within the c-fos promoter targeted by Rb.
Main Methods:
- Experiments were conducted on serum-induced and cycling 3T3 cells.
- Reporter gene assays were used to assess the effect of Rb on c-fos promoter activity.
- A cis-acting element conferring Rb-mediated repression was mapped within the human c-fos promoter.
Main Results:
- Rb was found to repress c-fos expression in 3T3 cells.
- Rb also repressed AP-1 transcriptional activity.
- A novel DNA sequence, termed the retinoblastoma control element, was identified in the c-fos promoter that mediates Rb repression.
Conclusions:
- The Rb protein directly represses c-fos gene expression and AP-1 activity.
- The retinoblastoma control element is a key regulatory site for Rb-mediated transcriptional repression of c-fos.