Associate Professor, Department of Medicine, Division of Hematology - Oncology
Member, UAB Comprehensive Cancer Center

Education:
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

Research Interests:
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 organization of these genes is complex. Recently, polymorphisms in the PDE4D gene have been shown to be associated with strokes in at least one human population. The PDE4 enzymes are also 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.

Selected Publications:

Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB (1999) The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. J Biol Chem 274:14909-14917.

Beard MB, Olsen AE, Jones RE, Erdogan S, Houslay MD, Bolger GB (2000) UCR1 and UCR2 domains unique to the cAMP-specific phosphodiesterase family form a discrete module via electrostatic interactions. J Biol Chem 275:10349-10358.

McCahill A, Warwicker J, Bolger GB, Houslay MD, Yarwood SJ (2002) The RACK1 scaffold protein: a dynamic cog in cell response mechanisms. Mol Pharmacol 62:1261-1273.

Bolger GB (2003) Molecular cloning and subcellular distribution of the novel PDE4B4 cAMP-specific phosphodiesterase isoform. Biochem J 370:429-438.

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.

D’Sa, C., Eisch, A.J., Bolger, G.B., Duman, R. (2005)  Differential expression and regulation of the cAMP-selective phosphodiesterase Type 4A splice variants in rat brain by chronic antidepressant administration. Eur. J. Neurosci, 22:1463-1475.

Bolger, G.B., Conti, M., Houslay, M.D. (2006) Cellular Functions of PDE4 Enzymes, in Beavo, J.A., Francis, S., Houslay, M.D., eds., Phosphodiesterases in Health and Disease, in Press

Bolger, G.B., (2006) PDE4 Isoforms, an Annotated List, in Beavo, J.A., Francis, S., Houslay, M.D., eds., Phosphodiesterases in Health and Disease, in Press

To contact Dr. Bolger:
1824 6th Avenue South
Wallace Tumor Institute 520A
Birmingham, AL 35294-3300
Phone: (205) 934-2992
Fax: (205) 975-6911
E-mail: E-mail: Graeme.Bolger@ccc.uab.edu