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Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter
Siqin Wu1, Cihan Cetinkaya, Maria J Munoz-Alonso
1Upsala Genetic Center, Department of Plant Biology, Swedish University of Agricultural Sciences.
Abstract:
Inhibition of cellular differentiation is one of the well-known biological activities of c-Myc-family proteins. We show here that Myc represses differentiation-induced expression of the cyclin-dependent kinase (CDK) inhibitor p21CIP1 (CDKN1A, p21), known to play an important role in cell fate decisions during growth and differentiation, in hematopoietic cells. Our results demonstrate that the c-Myc-responsive region is situated in the p21 core promoter. c-Myc binds to this region in vitro and in vivo through interaction with the initiator-binding Zn-finger transcription factor Miz-1, which associates directly with the promoter. Association of Myc with the promoter in vivo correlates inversely with p21 expression. Using mutants of c-Myc with impaired binding to Miz-1, our results further show that repression of p21 promoter/reporters as well as the endogenous p21 gene by Myc depends on interaction with Miz-1. Expression of Miz-1 increases during hematopoietic differentiation and Miz-1 activates the p21 promoter under conditions of low Myc levels, indicating a positive role for free Miz-1 in this process. In conclusion, repression of differentiation-induced p21 expression through Miz-1 may be an important mechanism by which Myc blocks differentiation.
Insights
The c-Myc protein inhibits cellular differentiation by repressing p21 expression in hematopoietic cells. This repression relies on Myc
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Biology
Background:
- c-Myc proteins are known to inhibit cellular differentiation.
- p21 (CDKN1A) is a cyclin-dependent kinase inhibitor crucial for cell fate decisions.
- Hematopoietic cells undergo differentiation, a process influenced by cell fate regulators.
Purpose of the Study:
- To investigate the mechanism by which c-Myc inhibits differentiation-induced p21 expression in hematopoietic cells.
- To identify the role of the transcription factor Miz-1 in c-Myc-mediated repression of p21.
Main Methods:
- Analysis of c-Myc binding to the p21 promoter region in vitro and in vivo.
- Use of reporter gene assays to study p21 promoter activity.
- Employing mutants of c-Myc to assess the dependence on Miz-1 interaction.
- Measuring expression levels of Miz-1 during hematopoietic differentiation.
Main Results:
- c-Myc represses differentiation-induced p21 expression in hematopoietic cells.
- The c-Myc-responsive region is located in the p21 core promoter.
- c-Myc interacts with Miz-1 to bind the p21 promoter, leading to repression.
- Miz-1 expression increases during differentiation and activates the p21 promoter when Myc levels are low.
Conclusions:
- Myc-mediated repression of differentiation-induced p21 expression occurs via interaction with Miz-1.
- This mechanism is a key way Myc blocks hematopoietic cell differentiation.
- Miz-1 plays a dual role, activating p21 when free and facilitating repression when bound by Myc.