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Autoregulation and heterogeneity in expression of human Cripto-1
Pojul Loying1, Janvie Manhas2, Sudip Sen2
1Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati, India.
Plos One
|February 7, 2015
Summary
Cripto-1 (CR-1) can induce its own expression through a positive feedback loop, increasing cell heterogeneity. This CR-1 positive subpopulation also shows higher expression of drug efflux protein MDR-1.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cancer Biology
Background:
- Cripto-1 (CR-1) is a key protein in embryonic development and cancer progression.
- CR-1 expression is tightly regulated by multiple signaling pathways.
- Gene expression stochasticity leads to cellular heterogeneity.
Purpose of the Study:
- To investigate a potential positive feedback loop where CR-1 induces its own expression.
- To elucidate the signaling pathway involved in CR-1 auto-induction.
- To examine the role of CR-1 positive feedback in cellular heterogeneity and cancer phenotypes.
Main Methods:
- Treatment of U-87 MG cells with exogenous CR-1.
- Analysis of the ALK4/SMAD2/3 signaling pathway.
- Flow cytometry to assess CR-1 expression heterogeneity.
- Measurement of multidrug resistance protein 1 (MDR-1) expression.
Main Results:
- Exogenous CR-1 treatment induced CR-1 expression via the ALK4/SMAD2/3 pathway.
- CR-1 auto-induction increased the proportion of CR-1 positive cells, demonstrating bimodal expression.
- The CR-1 positive subpopulation exhibited elevated MDR-1 expression, suggesting correlated induction.
- Most cells remained CR-1 negative even at high CR-1 doses.
Conclusions:
- A positive feedback circuit for CR-1 expression exists, involving the ALK4/SMAD2/3 pathway.
- This feedback mechanism enhances cellular heterogeneity, creating distinct CR-1 high and low subpopulations.
- CR-1 driven heterogeneity may contribute to cancer cell phenotypic diversification and drug resistance.
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