ΔNp63 regulates select routes of reprogramming via multiple mechanisms
E M Alexandrova1, O Petrenko, A Nemajerova
1Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
Cell Death and Differentiation
|September 10, 2013
Summary
The tumor suppressor p63 protein enhances induced pluripotent stem cell (iPSC) generation efficiency by facilitating gene expression and cell proliferation, revealing distinct reprogramming routes. p73 has no role in this process.
Area of Science:
- Stem Cell Biology
- Epigenetics
- Molecular Mechanisms of Reprogramming
Background:
- Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) is a key technology, but its underlying molecular mechanisms remain incompletely understood.
- While p53 deficiency is known to enhance iPSC generation, the roles of its homologs, p63 and p73, are unexplored.
- Evidence suggests reprogramming can occur via multiple distinct pathways.
Purpose of the Study:
- To investigate the roles of p63 and p73 homologs in the efficiency and mechanisms of induced pluripotency.
- To determine if p63 and p73 act as barriers or enablers in different reprogramming factor combinations.
- To elucidate the specific contributions of p63 isoforms and downstream effects on reprogramming pathways.
Main Methods:
- Utilized mouse embryonic fibroblasts (MEFs) for reprogramming experiments with different transcription factor combinations (OSK, OS, OK).
- Assessed the impact of p53, p63, and p73 knockout or deficiency on iPSC generation efficiency.
- Analyzed gene expression (mesenchymal-epithelial transition, pluripotency markers), cell proliferation, and isoform-specific roles (ΔNp63 vs. TAp63).
Main Results:
- p73 deficiency did not affect reprogramming, while p63 deficiency significantly reduced efficiency for OSK and OS, but not OK reprogramming.
- p63 acts as an enabling factor, essential for optimal reprogramming efficiency by promoting gene expression and proliferation, particularly the ΔNp63 isoform.
- Distinct mechanisms govern OSK (epithelial and pluripotency gene regulation) and OS (proliferation regulation) reprogramming, highlighting pathway-specific p63 requirements.
Conclusions:
- p63, but not p73, is a critical enabling factor for efficient iPSC generation via specific transcription factor combinations.
- The study identifies three distinct reprogramming routes (OSK, OS, OK) based on differential p63 dependency, supporting the concept of multiple reprogramming pathways.
- Understanding p63's role offers insights into optimizing iPSC generation and the fundamental biology of cellular plasticity.
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