Related Experiment Videos
Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth
Peter M Siegel1, Weiping Shu, Joan Massagué
1Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Abstract:
The growth inhibitory cytokine TGF-beta enforces homeostasis of epithelia by activating processes such as cell cycle arrest and apoptosis. Id2 expression is often highest in proliferating epithelial cells and declines during differentiation. Recently, Id2 expression has been found to depend on Myc-Max transcriptional complexes. We observed that TGF-beta signaling inhibits Id2 expression in human and mouse epithelial cell lines from different tissue origins. Furthermore, the observed Id2 down-regulation by TGF-beta in mouse mammary epithelial cells occurs without a concurrent drop in c-Myc levels. However, sustained Id2 repression in these cells and in human keratinocytes coincides with induction of the Myc antagonistic repressors Mad2 and Mad4, decreased formation of Myc-Max heterodimers and the replacement of Myc-Max complexes with Mad-Max complexes on the Id2 promoter. These results argue that induction of Mad expression and Id2 down-regulation are important events during the TGF-beta cytostatic program in epithelial cells.
Insights
Transforming growth factor-beta (TGF-β) inhibits Id2 expression in epithelial cells by inducing Mad proteins. This mechanism is crucial for TGF-β
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-beta (TGF-β) is a cytokine that maintains epithelial homeostasis through cell cycle arrest and apoptosis.
- Id2 expression is typically high in proliferating epithelial cells and decreases during differentiation.
- Id2 expression is regulated by Myc-Max transcriptional complexes.
Purpose of the Study:
- To investigate the effect of TGF-β signaling on Id2 expression in epithelial cells.
- To elucidate the molecular mechanisms underlying TGF-β-mediated Id2 down-regulation.
Main Methods:
- Utilized human and mouse epithelial cell lines from various tissue origins.
- Analyzed changes in Id2, c-Myc, Mad2, and Mad4 expression levels.
- Assessed the composition of transcriptional complexes on the Id2 promoter using techniques like chromatin immunoprecipitation (ChIP).
Main Results:
- TGF-β signaling significantly inhibits Id2 expression in diverse epithelial cell lines.
- Id2 down-regulation by TGF-β in mammary cells occurred independently of c-Myc level reduction.
- TGF-β induced Mad2 and Mad4 expression, leading to reduced Myc-Max and increased Mad-Max complexes at the Id2 promoter.
Conclusions:
- TGF-β signaling suppresses Id2 expression in epithelial cells.
- Induction of Mad repressors and subsequent replacement of Myc-Max with Mad-Max complexes are key events in TGF-β-induced Id2 down-regulation.
- These findings highlight the role of Mad induction and Id2 repression in the TGF-β cytostatic program within epithelial cells.