specific effect of p53 on life span (19); the consequences of modulating p53 were found to be also tissue and stage specific (19). Indeed, ubiquitous overexpression of p53 in adults shortens life span in females but slightly increases life span in males (20), whereas neuronal expression of the same construct extends life span in females and decreases life span in males (21). Overexpressing p53 in larval stages, on the other hand, is sufficient to extend adult life span in both sexes, but in a dose-dependent manner, where strong expression is deleterious for life span, whereas moderate- to-weak overexpression increases life span (20). A recent

Extensive research over the past two decades has placed p53 at the hub of a very complex network of signaling path- ways that integrate a variety of intracellular and extracel- lular inputs. Thus, it is becoming increasingly clear that the opposing effects of various components of the p53 signal- ing network must be carefully balanced to correctly regulate p53 function and induce the appropriate cellular response (29,30). Under normal conditions, p53 is expressed at a

low level and has a short half-life. When cells are exposed to a stressful environment, p53 is activated, resulting in transcriptional regulation of many target genes, including the MDM2 gene. A reduced MDM2-mediated degradation of p53–R72 variant compared with p53–P72 variant was recently reported (31). Notably, a single nucleotide poly- morphism in the MDM2 promoter (SNP309), leading to elevated MDM2 expression and attenuated efficiency of the p53 pathway, is regulated by estrogen signaling (32–34). Interestingly, SNP309 (G/G) seems to have a more signifi- cant effect on accelerating tumor formation in a gender-spe- cific (women) and hormonal-dependent manner (35–37). Also, recent results suggest the possibility that SNP309 G allele may contribute to gender-specific tumorigenesis through further elevating the MDM2 levels and disrupting the p53–MDM2 oscillation (38). Indeed, a gender-specific gene–gene interaction between the two polymorphisms was found in nonoropharyngeal cancer, where the youngest age at onset was observed in female patients with the combined MDM2 SNP309 G/G and TP53 codon 72 P*/P* genotypes (39). In breast cancer, homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53*P72 carriers (25).

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