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MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis
G Ganguli1, J Abecassis, B Wasylyk
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, F-67404 Illkirch cedex France.
Abstract:
The MDM2 oncogene is overexpressed in 5-10% of human tumours. Its major physiological role is to inhibit the tumour suppressor p53. However, MDM2 has p53-independent effects on differentiation and does not predispose to tumorigenesis when it is expressed in the granular layer of the epidermis. These unexpected properties of MDM2 could be tissue specific or could depend on the differentiation state of the cells. Strikingly, we found that MDM2 has p53-dependent effects on differentiation, proliferation and apoptosis when it is expressed in the less differentiated basal layer cells. MDM2 inhibits UV induction of p53, the cell cycle inhibitor p21(WAF1/CIP1) and apoptosis ('sunburn cells'). Importantly, MDM2 increases papilloma formation induced by chemical carcinogenesis and predisposes to the appearance of premalignant lesions and squamous cell carcinomas. p53 has a natural role in the protection against UV damage in the basal layer of the epidermis. Our results show that MDM2 predisposes to tumorigenesis when expressed at an early stage of differentiation, and provide a mouse model of MDM2 tumorigenesis relevant to p53's tumour suppressor functions.
Insights
The MDM2 oncogene inhibits tumor suppressor p53. When expressed in basal skin cells, MDM2 promotes tumor formation, highlighting its role in carcinogenesis and p53
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- MDM2 oncogene overexpression is observed in 5-10% of human tumors.
- MDM2's primary function is inhibiting the tumor suppressor p53.
- MDM2 exhibits p53-independent effects on cell differentiation, not causing tumors in differentiated epidermal cells.
Purpose of the Study:
- To investigate the role of MDM2 in cell differentiation, proliferation, and apoptosis.
- To determine the impact of MDM2 expression in different epidermal cell layers on tumorigenesis.
- To elucidate the p53-dependent and independent functions of MDM2 in the context of UV damage and chemical carcinogenesis.
Main Methods:
- Expression analysis of MDM2 in different epidermal cell layers (basal vs. granular).
- Assessment of MDM2's effects on UV-induced p53, p21(WAF1/CIP1), and apoptosis.
- Evaluation of MDM2's influence on chemically induced papilloma formation and squamous cell carcinoma development in a mouse model.
Main Results:
- MDM2 exhibits p53-dependent effects on differentiation, proliferation, and apoptosis specifically in less differentiated basal layer cells.
- MDM2 inhibits UV-induced p53, p21(WAF1/CIP1), and apoptosis ('sunburn cells').
- MDM2 expression significantly increases chemically induced papilloma formation and progression to squamous cell carcinomas.
Conclusions:
- MDM2 predisposes to tumorigenesis when expressed early in the differentiation process within the epidermis.
- MDM2's tumor-promoting effects are context-dependent, particularly on the differentiation state of the cells.
- This study provides a relevant mouse model for MDM2-driven tumorigenesis, underscoring p53's tumor suppressor functions in the skin.