Tumor suppressor function of a dominant negative retinoic acid receptor mutant
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Updated: Oct 29, 2026
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
D L Crowe1, U E Osaseri, C F Shuler
1Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles 90033, USA.
Abstract:
Mutations in receptors for the vitamin A metabolite retinoic acid (RAR) that repress retinoic acid (RA)-responsive gene expression have been identified and characterized. We previously reported an absence of target gene response to RA in all but one of a series of transformed human epithelial cell lines. To elucidate the mechanisms of this unresponsiveness, we created stable transfectants that expressed an RARalpha mutant (RARalpha403) previously shown to have dominant negative activity due to a C-terminal truncation. All clones exhibited repressed RA-responsive gene expression. These cells grew slowly and demonstrated greater growth inhibition by RA. Pretreatment of both control and experimental groups with RA enhanced epidermal growth factor-induced proliferation despite RA-dependent downregulation of epidermal growth factor receptor expression. In addition, clones expressing the mutant RARalpha were 60% less invasive in an in vitro assay. This reduced invasiveness correlated with decreased gelatinase activity in these cells. We showed for the first time that a dominant negative mutation in RARalpha can function as a tumor suppressor in transformed epithelial cells.
Insights
A dominant negative mutation in retinoic acid (RA) receptors (RAR) acts as a tumor suppressor in epithelial cells. This RARalpha mutation repressed gene expression, inhibited cell growth, and reduced invasiveness.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Retinoic acid (RA) is a vitamin A metabolite crucial for gene regulation.
- Mutations in RA receptors (RAR) can disrupt normal cellular functions.
- Previous studies showed unresponsiveness to RA in transformed epithelial cells.
Purpose of the Study:
- To investigate the mechanisms of RA unresponsiveness in transformed epithelial cells.
- To characterize the function of a dominant negative RARalpha mutant (RARalpha403).
- To determine if RARalpha mutations can act as tumor suppressors.
Main Methods:
- Created stable transfectants expressing the RARalpha403 mutant.
- Assessed RA-responsive gene expression.
- Evaluated cell growth, proliferation, and invasiveness.
- Measured gelatinase activity.
Main Results:
- All RARalpha403 expressing clones showed repressed RA-responsive gene expression.
- Cells exhibited slower growth and greater growth inhibition by RA.
- RA pretreatment enhanced EGF-induced proliferation despite EGFR downregulation.
- RARalpha403 expressing clones were 60% less invasive with decreased gelatinase activity.
Conclusions:
- A dominant negative RARalpha mutation can repress RA-responsive gene expression.
- This mutation can inhibit cell proliferation and invasiveness in transformed epithelial cells.
- The RARalpha403 mutant functions as a tumor suppressor in these cells.
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