Abstract
MDM2 plays a key role to physiological processes like growth arrest, senescence and apoptosis. It binds to and inhibits key proteins like p53 and the RB protein, and MDM2 amplification as well as protein overexpression without amplification is seen in many solid tumors. An MDM2 promoter polymorphism (SNP309T>G) has been found associated with enhanced Sp1 transcription factor binding and elevated MDM2 transcription. While 309G has been found associated with elevated cancer risk and young age at diagnosis of different cancers, results in Caucasians have been at variance. Recently, we reported a second polymorphism (SNP285G>C) located on the 309G allele. The 285C/309G haplotype accounts for about 12% of all 309G alleles among Norwegians, Dutch and British habitants. Assessing Sp1 binding to the MDM2 promoter using surface plasmon resonance technology, we found SNP309G to enhance Sp1 binding by 22% while SNP285C reduced Sp1 binding by 51%. SNP285C reduced the risk of breast cancer and ovarian cancer among 309TG/309GG carriers by 21 and 26%, respectively, but in particular the risk of ovarian cancer among 309TG heterozygotes (reduction by 37%). The fact that the 285C/309G haplotype accounted for only 1.9% of all 309G alleles among Finns and was absent in Chinese indicate 285C to be a young polymorphism.
Highlights
Murine Double Minute Clone 2 (MDM2) plays a key role in the regulation of cell cycle and apoptosis
Another alternative mechanism of MDM2 upregulation, disturbing proper function of the p53 pathway, was reported: Inuzuka and co-workers demonstrated that MDM2 is phosphorylated by Casein Kinase I (CKI), marking the MDM2 molecule for degradation via the SCFβ-TRCP Ubiquitin ligase [17]
This has been suggested as a potential mechanism of MDM2 upregulation in cases where CKI and / or β-TRCP are inactivated [18], a hypothesis that is supported by the findings of β-TRCP-deletions in several tumor forms [1820]
Summary
Murine Double Minute Clone 2 (MDM2) plays a key role in the regulation of cell cycle and apoptosis. Most of the studies linking the SNP309G variant allele to enhanced cancer risk or a young age at diagnosis have been performed
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
