Related Experiment Videos
Hic-5 regulates an epithelial program mediated by PPARgamma.
Stavit Drori1, Geoffrey D Girnun, Liqiang Tou
1Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes & Development
|February 3, 2005
Summary
Peroxisome proliferator-activated receptor gamma (PPARγ) interacts with Hic-5, a coactivator protein. This interaction is crucial for regulating epithelial cell differentiation in the gut and other tissues.
Area of Science:
- Molecular Biology
- Cell Differentiation
- Nuclear Receptors
Background:
- Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipogenesis and epithelial cell differentiation.
- The precise mechanisms by which PPARγ influences diverse cell lineages, particularly in the gut epithelium, remain largely unknown.
- Understanding PPARγ's role is critical for comprehending normal development and disease states like cancer.
Purpose of the Study:
- To elucidate the mechanism by which PPARγ regulates epithelial cell differentiation.
- To investigate the role of the coactivator protein Hic-5 in PPARγ-mediated differentiation.
- To determine if Hic-5 influences PPARγ's function in both normal development and cancer.
Main Methods:
- Investigated the interaction between PPARγ and Hic-5 using co-localization studies in intestinal tissues.
- Analyzed the expression patterns of PPARγ and Hic-5 during embryonic gut development and in tumors.
- Utilized gain-of-function (forced expression) and loss-of-function (siRNA) approaches in colon cancer cells and preadipocytes.
- Assessed the impact on differentiation markers (e.g., L-FABP, KLF4, keratin 20) and adipogenesis.
Main Results:
- PPARγ interacts with the coactivator Hic-5 in the villus epithelium of the small intestine.
- Expression of both PPARγ and Hic-5 correlates with epithelial differentiation during embryonic development and is reduced in tumors.
- Hic-5 enhances PPARγ-mediated induction of gut epithelial differentiation markers in colon cancer cells and ex vivo gut models.
- Forced expression of Hic-5 inhibits adipogenesis and induces gut epithelial gene expression in preadipocytes.
Conclusions:
- Hic-5 acts as a crucial coactivator, mediating PPARγ's role in establishing an epithelial differentiation program.
- The PPARγ-Hic-5 interaction is vital for normal gut epithelial development and its dysregulation is linked to cancer.
- Hic-5's function extends beyond adipogenesis, influencing cell fate decisions in diverse lineages.