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Switch from p53 to MDM2 as differentiating human keratinocytes lose their proliferative potential and increase in
J E Dazard1, J Piette, N Basset-Seguin
1Institut de Génétique Moléculaire, (CNRS, UMR 5535), Montpellier, France.
Abstract:
p53 transcription factor is mutated in most skin cell carcinomas and in more than 50% of all human malignancies. One of its transcriptional targets is MDM2, which in turn down-regulates p53. The role of the p53/MDM2 regulatory loop upon genotoxic stress is well documented, but less is known about its role in normal tissue homeostasis. We have explored this pathway during the different transitions of the human epidermal differentiation programme and after isolating stem cells, transit amplifying cells or differentiating cells from epidermis. Maximum expression of p53 was found in proliferating keratinocytes. A striking and transient induction of MDM2 and a down-modulation of p53 characterized the transition from proliferation to differentiation in primary human keratinocytes. These changes were delayed in late differentiating carcinoma cells, and were clearly different in suspended primary fibroblasts. Interestingly, these changes correlated with an increase in cell size, at the time of irreversible commitment to differentiation. Induction of MDM2 was also associated with suppression of proliferation in normal, or hyperproliferative, psoriatic epidermis. Moreover, both proteins were induced as keratinocytes were driven to leave the stem cell compartment by c-Myc activation. Overall, our results show a critical regulation of the p53/MDM2 pathway at the epidermal transition from proliferation to differentiation.
Insights
The p53/MDM2 pathway is crucial for skin cell differentiation. Its regulation shifts during epidermal transitions, impacting cell proliferation and homeostasis.
Area of Science:
- Cell Biology
- Molecular Biology
- Dermatology
Background:
- The p53 transcription factor is frequently mutated in human cancers, including skin cell carcinomas.
- The p53/MDM2 regulatory loop is vital for responding to DNA damage, but its role in normal tissue homeostasis is less understood.
Purpose of the Study:
- To investigate the p53/MDM2 pathway's function during human epidermal differentiation.
- To analyze the pathway's activity in different epidermal cell populations (stem, transit amplifying, differentiating).
Main Methods:
- Isolation of epidermal stem cells, transit amplifying cells, and differentiating cells.
- Analysis of p53 and MDM2 expression levels during keratinocyte differentiation.
- Examination of the pathway in normal, psoriatic, and carcinoma cells.
Main Results:
- p53 expression peaked in proliferating keratinocytes.
- A transient induction of MDM2 and downregulation of p53 marked the proliferation-to-differentiation transition.
- These changes were delayed in carcinoma cells and correlated with increased cell size.
- MDM2 induction suppressed proliferation in normal and psoriatic epidermis.
- p53 and MDM2 were induced upon c-Myc activation, driving keratinocytes from the stem cell compartment.
Conclusions:
- The p53/MDM2 pathway is critically regulated during epidermal differentiation.
- This pathway plays a significant role in maintaining normal tissue homeostasis and responding to proliferative signals.