|Graeme Bolger, MD|
Hematology & Oncology
Campus Address: SHEL 1211
1720 2nd Avenue South, SHEL 1211
Birmingham, AL 35294-2182
Phone: (205) 934-2992
For an appointment, call (205) 934-9999 or toll free 1 (800) UAB-8816.
Secondary: Pharmacology & Toxicology
Associate Professor, Department of Medicine, Division of Hematology – Oncology
Member, UAB Comprehensive Cancer Center
B.Sc. in Molecular, Cellular and Developmental Biology, McGill University;
M.D., McGill University (Montreal, Canada);
Residency, Internal Medicine, Johns Hopkins University;
Clinical Fellowships, Medical Oncology, Fred Hutchison Cancer Research Center and Memorial Sloan-Kettering Cancer Center;
Post-Doctoral Research Fellowship, Cold Spring Harbor Laboratory
1. Molecular Pharmacology of cAMP Signaling Pathways:
We are studying the regulation of cAMP-specific phosphodiesterases, or PDE4 enzymes, which are involved in the regulation of levels of the "second messenger" cAMP in cells. We have shown that the human PDE4 enzymes are coded by four different genes, PDE4A, PDE4B, PDE4C, and PDE4D, and that each of these genes encodes multiple isoforms by the use of alternative mRNA splicing and initiation of transcription off multiple promoters. The PDE4 enzymes are targets for drugs that have potential antidepressant, smooth muscle relaxant and immunomodulatory actions in humans.
Over the past 5 years, we have determined that many PDE4 isoforms are components of large multi-protein complexes that regulate their biochemical properties, their subcellular localization, and their response to extracellular stimuli. The assembly of these complexes requires "scaffold" or "adaptor" proteins. We have identified a number of proteins that bind to the PDE4s and that are likely to serve as scaffolds or adaptors, including RACK1, a beta-propeller protein, and XAP2, an immunophilin. We have also demonstrated that one PDE4 isoform, PDE4D5, interacts specifically with the beta-arrestins, important scaffold proteins that regulate G-protein coupled receptor signaling.
2. Molecular Genetics of Prostate Cancer:
To bring new research objectives into the lab, and also to reflect our clinical interests, we have initiated a project to clone novel tumor suppressor genes involved in the pathogenesis of prostate cancer. Like all tumor suppressors, these genes undergo allele loss in cancers. We have identified these genes by their ability to revert the neoplastic phenotype of cancer cell lines. Ongoing research is focused on the cell biology and biochemical properties of the genes and their potential role in genetic predisposition to cancers in humans.
Prostate cancer and testicular tumors.
Bolger GB, Peden AH, Steele MR, MacKenzie C, McEwan DG, Wallace DA, Huston E, Baillie GS, Houslay MD (2003) Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J Biol Chem 278:33351-33363.
Bolger GB, McCahill A, Huston E, Cheung YF, McSorley T, Baillie GS, Houslay MD (2003) The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with B-arrestins. J Biol Chem. 278:49230-49238.
Bolger, G.B., Conti, M., Houslay, M.D. (2007) Cellular Functions of PDE4 Enzymes, in Beavo, J.A., Francis, S., Houslay, M.D., eds., Phosphodiesterases in Health and Disease, Boca Raton: CRC Press
Bolger, G.B., Baillie, G.S., Li, X., Lynch, M.J., Herzyk, P., Mohamed, A., Mitchell, L.H., McCahill, A., Hundsrucher, C., Klussmann, E., Adams, D.R., Houslay, M.D. (2006) Scanning peptide array analyses identify overlapping binding sites for the signaling scaffold proteins, beta-arrestin and RACK1 in the cAMP-specific phosphodiesterase, PDE4D5. Biochem. J. 398:23-36.
Murdoch, H., Mackie, S., Collins, D.M., Hill, E.V., Bolger, G.B., Klussmann, E., Porteous, D.J., Millar, J.K., Houslay, M.D. (2007) Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J.Neurosci. 27:9513-24.
MacKenzie, K.F., Topping, E.C., Bugaj-Gaweda, B., Deng, C., Cheung, Y.F., Olsen, A.E., Stockard, C.R., Mitchell, L.H., Baillie, G.S., Grizzle, W.E., DeVivo, M., Houslay, M.D., Wang, D., Bolger, G.B. (2008) Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change. Biochem J. 411: 361-9.
Leontiou, C.A., Gueorguiev. M., van der Spuy, J., Quinton, R., Lolli, F., Hassan, S., Chahal, H.S., Igreja, S.C., Jordan, S., Rowe, J., Stolbrink, M., Christian, H.C., Wray, J., Bishop-Bailey, D., Berney, D.M., Wass, J.A.H., Popovic, V., Ribeiro-Oliveira. A,, Jr., Gadelha, M.R., Monson, J.P., Akker, S.A., Davis, J.R.E., Clayton, R.N., Yoshimoto, K., Iwata, T., Matsuno, A., Eguchi, K., Musat, M., Flanagan, D., Peters, G., Bolger, G.B., Chapple, J.P., Frohman, L.A., Grossman, A.B., Korbonits, M. (2008) The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J. Clin. Endocrinol. Metab. 93:2390-2401.
Publications: See a listing of publications on PubMed, a service of the National Library of Medicine.