Annotated Bibliography

1. Zhang, X., Miao, X., Guo, Y., Tan, W., Zhou, Y., Sun, T., Wang, Y., Lin, D. 2006. Genetic Polymorphisms in Cell Cycle Regulatory Genes MDM2 and TP53 Are Associated With Susceptibility to Lung Cancer. Human Mutation, 27(1): 110-117.

·      Genotyping MDM2 showed several significant single nucleotide polymorphisms (SNPs). MDM2 promoter polymorphisms show a significant impact on the risk of developing lung cancer as they interact with smoking. A particular SNP of interest that has been shown to be strongly correlated to binding affinity is SNP309, a T to G change in the first intron. This results in a increased affinity for binding stimulatory protein 1 (SP1) which causes higher levels of MDM2 RNA and protein to be produced. At SNP309, there has been shown to be a 7.5-fold increased risk assocatied with the MDM2 GG mutated genotype compared to the MDM2 TT wildtype genotype in lung cancer. This is due to the G allele having a higher binding affinity to Sp1, thereby resulting in increased MDM2 expression, as described

2. Reifenberger, G., Liu, L., Ichimura, K., Schmidt, E.E., Collins, V.P. 1993. Amplification and Overexpression of the MDM2 Gene in a Subset of Human Malignant Gliomas without p53 Mutations. Cancer Research, 53:2736-2739.

·      Due to MDM2’s known binding and inhibiting capability on p53 tumour suppressor protein, there is a strong argument made for MDM2 overexpression as one of the underlying causes of malignancy of gliomas.

3. Kussie, P.H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A.J., Pavletich, N.P. 1996. Structure of the MDM2 Oncoprotein Bound to the p53 Tumour Suppressor Transactivation Domain. Science, 274(5289): 948-953.

·      Higher frequency of splice variants lacking p53 binding domain sequences was found in late stage and high grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.

4. Barak Y., Gottlieb E., Juven-Gershon T. and Oren M. 1994. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev, 8: 1739–1749.

·      The MDM2 gene has two different promoters, leading to transcripts that may initiate translation at different start codons. There are 40 splice variants, but for the majority of these variants, it is presently unknown whether they are translated into proteins. There have been about seven unique transcripts that have been described in both mouse and human cells as of 1999; a result of alternative internal splice sites.

5. Reifenberger, G., Liu, L., Ichimura, K., Schmidt, E.E., Collins, V.P. 1993. Amplification and Overexpression of the MDM2 Gene in a Subset of Human Malignant Gliomas without p53 Mutations. Cancer Research, 53:2736-2739.

·      Measures MDM2 gene levels and its correlation to malignant gliomas.

6. Ladanyi, M., Cha, C., Lewis, R. 1993. MDM2 Gene Amplification in Metastatic Osteosarcoma. Cancer Research, 53:16-18.

·      Shows MDM2 gene levels and its correlation to osteosarcoma.

7. Bougeard, G., Baert-Desurmont, S., Tournier, I., Vasseur, S., Martin, C., Brugieres, L., Chompret, A., Bressac-de Paillerets, B., Stoppa-Lyonnet, D., Bonaiti-Pellie, C., Frebourg, T. 2006. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. Journal of Medical Genetics, 43:531-533.

·      Shows correlation for age of onset of tumors in patients with li-fraumeni syndrome (lacking 1 p53 allele, predisposition to cancer) and relative MDM2 gene levels.

Amanda

email: manda147@interchange.ubc.ca | Student Number: 92681071