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RESEARCH INTERESTS - Physiological Mechanisms Associated with P450 Cytochromes
PI - Colin Jefcoate
PI – Colin Jefcoate
Project A: Regulation of StAR
We are examining regulation of cholesterol conversion to steriods that activate nuclear receptors. This requires cholesterol metabolism at P450 sec that is located in the mitochondria of specialized cells. This depends on the StAR protein which is regulated by cAMP at the level of transcription, mRNA stability and protein modification. Our recent work implicates additional regulation by various MAP kinases that regulate StAR mRNA stability via specific elements at the 3′ end of the mRNA. We are engineering the StAR mRNA to alter the protein function and mRNA stabiltity
Project B: Ah receptor suppresses differentiation via MAP kinases
Here we are dissecting the mechanism of differentiation of multipotential embryo cells to adipcytes. This process is activated by the PPAR(Gamma) receptor. We have shown that activation of the Ah receptor blocks adipogenesis by suppressing PPAR(Gamma) expression. This depends on activation of MAP kinases. The Ah receptor also regulates a cytochrome P4+50 in these cells (CCYP1B1) which may metabolize an endogenous activator of differentiation.
Project C: Cytochrome P4501B1 is regulated by both AhR and cAMP
We are studying the molecular regulation of CYP1B1 expression and the role this protein plays in cancer caused by polycyclic aromatic hydrocarbons. Using a CYP1B1 – knockout mouse we showed that metabolism by CYP1B1 is essential for many cancers caused by these chemicals. We have identified two enhancers regions in the CYP1B1 gene: one is very responsive to the Ah receptor, one responds to cAMP. There mechanisms are being further characterized in multiple cell types including mammary epithelia that are targets for this carcinogenesis. We are looking for determinants of cell specific expression and also testing the hypothessis that the key role of CYP1B1 in carcinogenesis arises from expression in susceptible multi-potential cells.
The laboratory studies the toxicity of various agents by identifying molecular mechanisms by which these processes are disrupted. The toxicity of sodium arsenite, TCDD (Dioxin) and polycyclic hydrocarbons is being studied in Projects A, B and C respectively.