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Signal transduction pathways converging on the tumor suppressor p53 are central in the regulation of cell growth and cell death. Conventional chemotherapeutics result in p53 checkpoint activation. However when the p53 pathway is blocked a more targeted chemotherapeutic approach will be required to result in an outcome of cell death. A focus on such targeted approaches are central to the experiments being carried out in the Bargonetti laboratory.   The work in my laboratory focuses on the molecular signal transduction pathways activated by various chemotherapeutic drugs to bring about differential activation of p53 target genes as well as to activate alternative p53-independent cell death pathways that facilitate killing resistant cancer cells. Presently this work is carried out using human cancer cell line models and with a C. elegans nematode model system.  Most recently work in my laboratory has characterized that the nucleoside analogue 8-amino-adenosine kills metastatic breast cancers independently of activating the p53-pathway.

 

The Bargonetti research team is using genetically engineered tools to decrease the expression of three oncogenes (i.e. Mdm2, MdmX, and oncogenic mutant p53) because we hypothesize that these biomarkers are involved in the formation of different subtypes of breast cancer. We discovered that reducing the amount of Mdm2 or mutant p53 protein in breast cancer cells reduces tumor growth and abnormal architecture in three-dimensional (3D) cell culture models. We identified that estrogen receptor positive (ER+) breast cancer cells possess an Mdm2-associated growth activation pathway. Our work has been instrumental for introducing the concept of an estrogen driven signaling pathway that uses a non-canonical Mdm2 molecular mechanism. We are delineating the molecular targets of estrogen driven Mdm2 isoforms by using genetically engineered human breast cancer cell lines to selectively rid the cancer cells of either  Mdm2, MdmX, or oncogenic mutant p53 in order to  dissect the critical targets that promote tumorigenesis. Estrogen receptor positive (ER+) breast cancers often have high levels of Mdm2 and ER negative (ER-) breast cancers often have mutant p53. We are dissecting the relevant targets of Mdm2, MdmX, and oncogenic mutant p53 in different subtypes of breast cancer.

 

Many cancer cells have high levels of the oncogenic Mdm2 protein due to either increased expression or amplification of the mdm2 gene. The Bargonetti group investigates a single nucleotide polymorphism (SNP) at position 309 in the mdm2 gene that causes increased affinity for SP1, leading to Mdm2 overexpression from the gene ’s P2 promoter. In cells that have this 309 SNP, the p53 pathway is compromised. High levels of Mdm2 cause increased degradation of p53 protein, however the complexity of the inhibition of p53 by Mdm2 suggests alternative mechanisms for inhibition (and not just degradation) also play a role.

Last Updated ( Saturday, 28 March 2015 15:41 )