MDM2, a well-known inhibitor of p53, is overexpressed in a large number of tumors, suggesting that increased levels of MDM2 also contribute to tumorigenesis.
MDM2 itself is a transcriptional target of p53, and therefore, MDM2 forms a negative feedback loop with p53 to tightly regulate p53 levels and function. microRNAs (miRNAs) play a key role in regulation of gene expression. miRNA dysregulation plays an important role in tumorigenesis.
Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood.
Amplification of the MDM2 gene and overexpression of its protein have been observed in some human malignancies, and these abnormalities have a role in tumorigenesis through inactivation of p53 function.
As combinations of genetic and/or epigenetic alterations occurring during salivary gland carcinogenesis are largely unknown, we here analyzed 36 salivary gland carcinomas (SGCs) for changes in INK4a/ARF, RB1, p21, p27, PTEN, p53, MDM2 and O6-MGMT genes using methylation specific PCR (MSP), loss of heterozygosity (LOH) assays and mutational analysis with immunohistochemistry (IHC), as well as histone H3 and H4 acetylation status.
As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a well-described cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans.