G. Ganguli et al., MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis, EMBO J, 19(19), 2000, pp. 5135-5147
The MDM2 oncogene is overexpressed in 5-10% of human tumours, Its major phy
siological role is to inhibit the tumour suppressor p53. However, MDM2 has
p53-independent effects on differentiation and does not predispose to tumor
igenesis 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 premaligna
nt lesions and squamous cell carcinomas. p53 has a natural role in the prot
ection against UV damage in the basal layer of the epidermis. Our results s
how that MDM2 predisposes to tumorigenesis when expressed at an early stage
of differentiation, and provide a mouse model of MDM2 tumorigenesis releva
nt to p53's tumour suppressor functions.