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Ca2+ and BMP-6 signaling regulate E2F during epidermal keratinocyte differentiation.
S J D'Souza1, A Pajak, K Balazsi
1Departments of Pharmacology/Toxicology and Paediatrics, Child Health Research Institute and Lawson Health Research Institute, University of Western Ontario, London, Ontario N6A 5C1, Canada.
The Journal of Biological Chemistry
|April 25, 2001
Summary
Epidermal stem cells use E2F-1, -2, and -3 for proliferation. Upon differentiation, E2F-5 forms complexes with p130 and HDAC1, inhibiting DNA synthesis and promoting permanent cell cycle exit.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- The epidermis relies on stem cells for continuous renewal, balancing self-renewal and differentiation.
- Previous work indicated differential E2F gene expression during epidermal development.
- E2F proteins are hypothesized to have distinct roles in proliferating stem cells versus differentiated keratinocytes.
Purpose of the Study:
- To investigate the roles of E2F factors in epidermal morphogenesis.
- To examine the expression, regulation, and interactions of E2F factors in keratinocytes during differentiation.
Main Methods:
- Cultured murine primary keratinocytes were used.
- Cells were induced to differentiate using calcium (Ca2+) or bone morphogenetic protein 6 (BMP-6).
- Expression patterns, protein-protein interactions, and DNA synthesis inhibition were analyzed.
Main Results:
- Both Ca2+ and BMP-6 induced similar E2F expression patterns.
- A switch from E2F-1, -2, and -3 in proliferating cells to E2F-5 in differentiated cells was observed.
- E2F-5 upregulation correlated with p130 and histone deacetylase (HDAC) 1 complex formation.
- Transforming growth factor-beta1 did not increase E2F-5, indicating a differentiation-specific response.
- Overexpression of E2F-5 inhibited DNA synthesis in an HDAC-dependent manner.
Conclusions:
- E2F-5, p130, and HDAC1 complexes are involved in keratinocyte terminal differentiation.
- These complexes likely mediate permanent cell cycle withdrawal during epidermal development.