Jody Mack, Ph.D.
Postdoctoral Fellow
Ph.D. - University of South Carolina, Biological Sciences
Tel: 843-792-8985
Fax: 843-792-9588
mackj@musc.edu
Defining the roles of the ABCA2 transporter in vivo
In normal tissues, the ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein most highly expressed in the central and peripheral nervous system tissues, prostate, ovary and macrophages. ABCA2 is also highly expressed in several human cancers including T-cell acute lymphoblastic leukemia, childhood acute myeloid leukemia, vestibular schwannomas and oligodendrogliomas. Previous studies indicated its role in cholesterol/steroid transport, oxidative stress response, and resistance to hormones and sterol-containing chemotherapeutics (17β-estradiol, estramustine, progesterone). Developmental studies have shown its expression during macrophage and oligodendrocyte differentiation, processes requiring membrane growth.
To determine the physiological role(s) of this transporter, we generated a knockout mouse from a gene-targeted disruption of the murine Abca2 gene. Compared to wild-type (WT) and heterozygous littermates, knockout (KO) mice displayed a tremor, hyperactivity, and reduced body weight. Myelin sheath thickness in the spinal cords of KO mice was greatly increased compared to that in WT mice, while a significant reduction in myelin membrane periodicity (compaction) was observed in both spinal cords and cerebra of KO mice. This abnormal myelin compaction in spinal cord and cerebrum is proposed to be the ultrastructural defect underlying the phenotypic tremor in KO mice.
Ongoing studies include characterizing the in vivo response of KO mice and KO mouse embryonic fibroblasts (MEFs) to sterol-based (estramustine) chemotherapy. By crossing KO mice into a prostate carcinoma tumor model, we hope to uncover the role of Abca2 in the prostate tumor development and response to estramustine-based chemotherapy.
Selected Publications
Mack J.T., Beljanski V., Soulika A.M., Townsend D.M., Brown C.B., Davis W., and Tew K.D. “Skittish” Abca2 knockout mice display tremor, hyperactivity and abnormal myelin ultrastructure in the central nervous system. Mol. Cell. Biol. 27(1):44-53, 2007.
Mack J.T, Townsend D.M., Beljanski V., and Tew K.D. The ABCA2 transporter: Intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compound. Curr. Drug Metab. 8(1):47-57, 2007.
Mack J.T., Beljanski V., Tew K.D., and Townsend D.M. The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking. Biomed. Pharmacother. 60(9):587-92, 2006.
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