Faculty: Colin R. Jefcoate
|Dept:||Professor, Cell & Regenerative Biology|
|Training Areas:||Molecular & Cellular Pharmacology|
Our research addresses signaling mechanisms involving P450 cytochromes. These regulate activity at nuclear receptors regulated by three types of activator.
- cholesterol/steroid hormones
- fatty acids and metabolites
- Ah receptor/PCB's and polycyclic aromatic hydrocarbons
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.
Honors & Awards
- 2013-WARF Professorship
- 1998-2003 WARF Mid-Career Faculty Researcher Award
Other Positions & Affiliations
- Director, Environmental Health Sciences Center for Developmental Toxicology
- Zheng W, Tong T, Lee J, Liu X, Marcus C, Jefcoate CR. Stimulation of mouse Cyp1b1 during adipogenesis: Characterization of promoter activation by the transcription factor Pax6. Arch Biochem Biophys. 2013 Jan 29;532(1):1-14. doi: 10.1016/j.abb.2013.01.007. [Epub ahead of print] PMID: 23376040
- N'jai AU, Larsen MC, Bushkofsky JR, Czuprynski CJ, Jefcoate CR (2011). Acute disruption of bone marrow hematopoiesis by benzo(a)pyrene is selectively reversed by aryl hydrocarbon receptor-mediated processes. Mol Pharmacol. 79(4):724-34. PMID: 21252291
- Jefcoate CR, Lee J, Cherradi N, Takemori H, Duan H (2011). cAMP stimulation of StAR expression and cholesterol metabolism is modulated by co-expression of labile suppressors of transcription and mRNA turnover. Mol Cell Endocrinol. 336(1-2):53-62. PMID: 21147196
- N'jai AU, Larsen M, Shi L, Jefcoate CR, Czuprynski CJ (2010). Bone marrow lymphoid and myeloid progenitor cells are suppressed in 7,12-dimethylbenz(a)anthracene (DMBA) treated mice. Toxicology. 271(1-2):27-35. PMID: 20171256
- Tang Y, Scheef EA, Gurel Z, Sorenson CM, Jefcoate CR, Sheibani N (2010). CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress. Am J Physiol Cell Physiol. 298(3):C665-78. PMID: 20032512
- Tang Y, Scheef EA, Wang S, Sorenson CM, Marcus CB, Jefcoate CR, Sheibani N (2009). CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression. Blood. 113(3):744-54. PMID: 19005183
- Halberg RB, Larsen MC, Elmergreen TL, Ko AY, Irving AA, Clipson L, Jefcoate CR (2008). Cyp1b1 exerts opposing effects on intestinal tumorigenesis via exogenous and endogenous substrates. Cancer Res. 68(18):7394-402. PMID: 18794127
- Jefcoate CR, Wang S, Liu X (2008). Methods that resolve different contributions of clonal expansion to adipogenesis in 3T3-L1 and C3H10T1/2 cells. Methods Mol Biol. 456:173-93. PMID: 18516561
- Duan H and Jefcoate CR. (2007). The predominant cAMP-stimulated 3 x 5 kb StAR mRNA contains specific sequence elements in the extended 3'UTR that confer high basal instability. J Mol Endocrinol. 38:159-179. PMID 17242178