Dr. Martin Petkovich
P. Martin Petkovich
Office Phone: 613-533-6791
- Professor of Biochemistry and Pathology & Molecular Medicine
- BSc, McMaster University; PhD, University of Toronto
Dr. Petkovich's Lab
The main research focus in the Petkovich lab is understanding the role of retinoic acid signalling and metabolism in health and disease. Retinoic acid (RA) is the active metabolite of vitamin A and has several important physiological functions including regulation of cell proliferation and apoptosis, cell differentiation, and tissue morphogenesis. These attributes of RA have been exploited in the clinic for the treatment of skin diseases and make it a strong candidate for cancer prevention and differentiation therapy.
RA distribution is finely controlled by the balanced activities of retinaldhyde dehydrogenases (Raldhs) which control its synthesis and cytochrome P450 enzymes from the CYP26 family which control its degradation. Three CYP26 family members (A1,B1 and C1) have been discovered in our lab. Their distribution during embryogenesis clearly indicates that they have distinct roles in defining the distribution of RA in tissues undergoing morphogenesis. We have already generated a CYP26A1 gene-knockout (KO) mouse model, the phenotype of which is embryonic lethal exhibiting spina bifida, caudal agenesis and defects in vertebral and rhombomere identity. We are now developing KO animals for the other two members of the CYP26 family. Several ongoing studies in our lab are directed toward understanding the transcriptional regulation of expression of CYP26 genes. This will help us to delineate the genetic pathways leading to the formation of tissues and organs during embryogenesis.
In situ hybridization experiments showing expression of Cyp26A1 and Cyp26B1
in developing mouse limb buds.
We are presently working with Cytochroma Inc. www.cytochroma.com to develop inhibitors for the CYP26 enzymes: these compounds will be valuable research tools and potentially drugs to be used in the treatment of skin disease and cancer.
In a separate research initiative, we are exploring new opportunities in microfluidics technology as a collaborative effort with the departments of Chemistry and Chemical engineering. This technology will be used to build biosensors and diagnostic devices.
- Chuang, S.S., Helvig, C., Taimi, M., Ramshaw, H.A., Collop, A.H., Amad, M., White, J.A., Petkovich, M., Jones, G. and Korczak, B. (2003) CYP2U1, a novel human thymus and brain specific cytochrome P450 catalyzes omega- and (omega-1)-hydroxylation of unsaturated fatty acids involved in lipid signaling. J. Biol. Chem. Dec 3 (epub).
- Taimi, M., Helvig, C., Wisniewski, J., Ramshaw, H., White, J., Amad, M., Korczak, B., and Petkovich, M. (2004). A novel human cytochrome P450, CYP26C1 involved in metabolism of 9-cis and all-trans, isomers of retinoic acid. J. Biol. Chem. 279(1):77-85.
- Abu-Abed, S., DollÃƒÂ©, P., Metzger, D., Chambon, P. and Petkovich, M. (2003). Developing with lethal RA levels: genetic ablation of RAR-gamma restores the viability of mice lacking Cyp26A1. Development. 130(7):1449-59.
- Tahayato, A., DollÃƒÂ©, P. and Petkovich, P. M. (2003). Cyp26C1 encodes a novel retinoic acid-metabolizing enzyme expressed in the hindbrain, inner ear, first branchial arch and tooth buds during murine development. Gene Expr. Patterns. 3(4):449-54.
- Chithalen, J.V., Luu, L., Petkovich M., Jones, G. (2002). HPLC-MS/MS analysis of the products generated from all-trans-retinoic acid using recombinant human CYP26A. J. Lipid. Res. 43(7):1133-42.
- Niederreither K., Abu-Abed, S., Schuhbaur, B., Petkovich, M., Chambon, P., DollÃƒÂ©, P. (2002). Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat. Genet. 31(1):84-8.
- Abu-Abed, S., MacLean, G., Fraulob, V., Chambon, P., Petkovich, M. , DollÃƒÂ©, P. (2002). Differential expression of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during murine organogenesis. Mech. Dev. 110(1-2):173-7.
- Petkovich, P.M. (2001) Retinoic acid metabolism. J. Am. Acad. Dermatol. 45(5):S136-42.
- MacLean, G., Abu-Abed, S., Tahayato, A., DollÃƒÂ©, P., Chambon, P. and Petkovich, M. (2001) Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development. Mech Dev. 107(1-2):195-201.
- Luu, L., Ramshaw, H., Tahayato, A., Stuart, A., Jones, G., White, J. and Petkovich, M. (2001) Regulation of retinoic acid metabolism. Adv. Enzyme Regul., 41:159-175.
- Abu-Abed, S., DollÃƒÂ©, P., Metzger, D., Beckett, B., Chambon, P. and Petkovich, M. (2001) The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity and development of posterior structures. Genes and Dev., 15:226-240.
- Loudig, O., Babichuk, C., White, J., Abu-Abed, S., Mueller, C. and Petkovich, M. (2000) Retinoic acid inducibility of P450RAI(CYP26) promoter involves a highly conserved retinoic acid response element and a Sp1/Sp3 site. Mol Endocrinol., 14(9):1483-97.
- White, JA., Ramshaw, H., Taimi, M., Stangle, W., Zhang, A., Everingham, S., Creighton, S., Tam, SP., Jones, G. and Petkovich M. (2000) Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism Proc. Natl. Acad. Sci. U S A. 97:6403-6408.
- Beckett, B. and Petkovich, M. (1999) Evolutionary conservation in retinoid signalling and metabolism. Am. Zoologist, 39:783-795.
- Swindell, E.C., Thaller, C., Sockanathan, S., Petkovich, M., Jessel, T.M. and Eichele, G. (1999) Roles of retinoid metabolism during development. Dev. Biol., 216: 282-296.
- McCaffery, P., Wagner, E., O'Neil, J., Petkovich, M. and DrÃƒÂ¤ger, U.C. (1999) Dorsal and ventral retinal territories defined by retinoic acid synthesis, break-down and nuclear receptor expression. Mech. Dev. 82:119-130.
- Jones, G., Ramshaw, H., Zhang, A., Cook, R., Byford, V., White, J. and Petkovich, M. (1999) Expression and activity of vitamin D-metabolizing cytochrome P450s (CYP1-alpha and CYP24) in human non-small cell lung carcinomas. Endocrinology 140:3303-3310.
- Iuliannella, A., Beckett, B., Petkovich, M. and Lohnes, D. (1999) A molecular basis for retinoic acid-induced axial truncation. Dev. Biol. 205(1):33-48.
- White, J.A. and Petkovich, M. (1998) Identification and cloning of RA-regulated genes by mRNA differential display. Edited by: C.F.P. Redfer, In Methods in Molecular Biology: Retinoid Protocols, Humana Press Inc., Totowna, NJ. 89: 389-404.
- Marikar, Y., Wang, Z., Duell, E.A., Petkovich, M., Voorhees, J.J. and Fisher, G.J. (1998) Retinoic acid receptors regulate expression of retinoic acid 4-hydroxylase that specifically inactivates all-trans retinoic acid in human keratinocyte HaCaT cells. J. Invest. Dermatol. 111:434-439.
- Sonneveld, E., van den Brink, C.E., van der Leede, B-J. M., Schulkes, R-K. A.M., Petkovich, M., van der Burg, B. and van der Saag, P.T. (1998) Human retinoic acid (RA) 4-hydroxylase (CYP26) is highly specific for All-trans-RA and can be induced through RA receptors in human breast and colon carcinoma cells. Cell Growth Diff. 9:629-637.
- White, J.A., Beckett, B., Scherer, S.W., Hebrick, J.R. and Petkovich, P.M. (1998) P450 RAI (CYP26A1) maps to human chromosome 10q23-q24 and mouse chromosome 19C2-3. Genomics 48(2):270-272.
- Abu-Abed, S.S., Beckett, B.R., Chiba, H., Chithalen, J.V., Jones, G., Metzger, D., Chambon, P. and Petkovich, M. (1998) Mouse P450RAI (CYP26) expression and retinoic acid-inducible retinoic acid metabolism in F9 cells are regulated by RAR-gamma and RXR-alpha. J. Biol. Chem. 273:2409-2415.
- White, J.A., Beckett-Jones, B., Guo, Y-D. Dilworth, F.J., Bonasoro, J., Jones, G. and Petkovich, M. (1997) cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450 (CYP26). J. Biol. Chem. 272:18538-18541.
- White, J.A., Guo, Y-D., Baetz, K., Beckett-Jones, B., Bonasoro, J., Hsu, K.E., Dilworth, F.J., Jones, G. and Petkovich, M. (1996) Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. J. Biol. Chem. 271:29922-29927.
- White, J.A., Boffa, M.B., Jones, B. and Petkovich, M. (1994) A zebrafish retinoic acid receptor expressed in the regenerating caudal fin. Development 120:1861-1872.
- Petkovich, M. (1992) "Vitamin A regulation of gene expression: The role of retinoic acid receptors", In: Annu. Rev. Nutr. 12:443-471.
- Brand, N., Petkovich, M., Krust, A., Chambon, P., de The, H., Marchio, A., Tiollais, P. and Dejean A. (1988) Identification of a second human retinoic acid receptor. Nature 332:850-853.
- Petkovich, M., Brand, N.J., Krust, A. and Chambon, P. (1987) A human retinoic acid receptor which belongs to the family of nuclear receptor. Nature 330:444-450.