Loss of genomic integrity in cells harboring an inactive p53 tumor suppressor has grave consequences in oncology. Inactivation of wild type p53wt can originate from its somatic mutation or from its segregation in the cytosol, where it is inoperative as a transcription factor. Cytoplasmic segregation of p53wt in aggressive neoplasms, typified by inflammatory breast cancer and neuroblastoma, or in pre-neoplastic lesions, typified by adenomatous polyps does not involve its somatic mutation or its sequestration by viral oncoproteins. Thus, epigenetic inactivation of p53wt must involve other, unknown participants and processes. We will test three integrated hypotheses: 1) Elevated risks of cancers associated with acute or chronic inflammation originate, in part, from a chemical impairment of p53wt that deranges its conformation and favors its segregation in the cytosol, a cellular compartment that is incompatible with its tumor suppressor function. 2) Inactivation of p53wt by electrophilic eicosanoids, or other electrophilic mediators of inflammation, will diminish the efficacy of conventional anti- neoplastic agents and worsen prognosis. Oncogenesis may proceed at different rates or via different molecular pathways depending on the nature of p53wt inactivation (somatic mutation versus epigenetic inactivation). 3) Electrophilic lipid mediators of inflammation, typified by certain eicosanoids derived from the lipoxygenase and cyclooxygenase catalytic pathways of biosynthesis, contribute to this epigenetic form of p53 inactivation via: i) direct reaction with p53wt or ii) indirect reaction with proteins that govern the conformational and functional integrity of p53. Our preliminary data emerge from our observations that agents acting independently of p53wt may be experimentally indistinguishable from agents inactivating p53wt unless one deliberately examines these two, separate possibilities. Cells exposed to lipids with an electrophilic substituent accumulate a conformationally deranged form p53wt in their cytosol, exclude it from their nucleus, disable its transactivation of p53wt responsive genes, and thereby reduce their susceptibility to p53wt -dependent apoptosis. Discovery and characterization of a novel, epigenetic mechanism for the inactivation of p53wt is directly significant for diagnosis, treatment, and prognosis of cancer. Our related discovery of a process that enables cells to propagate apoptosis via p53wt- independent pathways is directly significant to the pharmacology of cancer. We anticipate that our investigations will identify a novel molecular process associated with elevated risks of cancer and a novel role for eicosanoids in the modulation of genomic stability.
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