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The cyclin D1 gene is transcriptionally repressed by caveolin-1
1Albert Einstein Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
The cyclin D1 gene encodes the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma pRB protein. Cyclin D1 protein levels are elevated by mitogenic and oncogenic signaling pathways, and antisense mRNA to cyclin D1 inhibits transformation by the ras, neu, and src oncogenes, thus linking cyclin D1 regulation to cellular transformation. Caveolins are the principal protein components of caveolae, vesicular plasma membrane invaginations that also function in signal transduction. We show here that caveolin-1 expression levels inversely correlate with cyclin D1 abundance levels in transformed cells. Expression of antisense caveolin-1 increased cyclin D1 levels, whereas caveolin-1 overexpression inhibited expression of the cyclin D1 gene. Cyclin D1 promoter activity was selectively repressed by caveolin-1, but not by caveolin-3, and this repression required the caveolin-1 N terminus. Maximal inhibition of the cyclin D1 gene promoter by caveolin-1 was dependent on the cyclin D1 promoter T-cell factor/lymphoid enhancer factor-1-binding site between -81 to -73. The T-cell factor/lymphoid enhancer factor sequence was sufficient for repression by caveolin-1. We suggest that transcriptional repression of the cyclin D1 gene may contribute to the inhibition of transformation by caveolin-1.
Insights
Caveolin-1 negatively regulates cyclin D1 gene expression, impacting cellular transformation. This finding suggests caveolin-1
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cyclin D1 is a key regulator of cell cycle progression, often dysregulated in cancer.
- Caveolins are involved in signal transduction and membrane dynamics.
- Previous studies link cyclin D1 to cellular transformation via oncogenic signaling pathways.
Purpose of the Study:
- To investigate the relationship between caveolin-1 and cyclin D1 expression.
- To determine the mechanism by which caveolin-1 affects cyclin D1 gene regulation.
- To explore the role of this interaction in cellular transformation.
Main Methods:
- Analysis of cyclin D1 and caveolin-1 expression levels in transformed cells.
- Manipulation of caveolin-1 expression using antisense and overexpression techniques.
- Reporter gene assays to assess cyclin D1 promoter activity.
- Site-directed mutagenesis of the cyclin D1 promoter.
Main Results:
- Caveolin-1 expression inversely correlates with cyclin D1 levels in transformed cells.
- Caveolin-1 overexpression represses cyclin D1 gene expression and promoter activity.
- Repression is mediated through the T-cell factor/lymphoid enhancer-1 binding site on the cyclin D1 promoter.
- The N-terminus of caveolin-1 is crucial for this repression.
Conclusions:
- Caveolin-1 acts as a transcriptional repressor of the cyclin D1 gene.
- This repression mechanism may contribute to caveolin-1's tumor-suppressive effects.
- Understanding this pathway offers potential therapeutic targets for cancer treatment.