p53 E3 ubiquitin protein ligase homolog regulates p53 in vivo in the adult mouse eye lens.

PURPOSE: p53 is a transcription factor that plays an important role in preventing cancer development. p53 participates in relevant aspects of cell biology, including apoptosis and cell cycle control and must be strictly regulated to maintain normal tissue homeostasis. p53 E3 ubiquitin protein ligase homolog (Mdm2) is an important negative regulator of p53. The purpose of this study was to determine if Mdm2 regulates p53 in vivo in the adult lens.

METHODS

We analyzed mice expressing human p53 transgene (Tgp53) selectively in the lens in the presence or absence of Mdm2. Mice with the required genotypes were obtained by crossing transgenic, mdm2 (+/-), and p53 (-/-) mice. Eye phenotype and lens histology and ultrastructure were analyzed in adult mice.

RESULTS

In a wild-type genetic background (mdm2 (+/+)), lens damage and microphthalmia were observed only in mice homozygous for Tgp53 ((t/t)). However, in an mdm2 null background, just one allele of Tgp53 (mdm2 (-/-)/Tgp53 (t/0) mice) was sufficient to cause lens damage and microphthalmia. Furthermore, Mdm2 in only one allele was sufficient to rescue these deleterious effects, since the mdm2 (+/-)/Tgp53 (t/0) mice had eye size and lens morphology similar to the control mice.

CONCLUSIONS

Mdm2 regulates p53 in the adult lens in vivo. This information may have relevance for analyzing normal and pathological conditions of the lens, and designing cancer therapies targeting Mdm2-p53 interaction.