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Journal of Environmental Pathology, Toxicology and Oncology

ISSN for PRINT: 0731-8898

Institutional price:	$672.00
Issues per year:	4

Best Paper Award Selection - Editorial Board Site

2004, Volume23

88 pages

DOI: 10.1615/JEnvPathToxOncol.v23.i1

Issue price - $160.00

Attractin: Cautionary Tales for Therapeutic Intervention in Molecules with Pleiotropic Functionality

Jonathan S. Duke-Cohan
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

Jeong H. Kim
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Abdallah Azouz
Department of Medicine, Harvard Medical School; and Department of Radiology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts, USA

ABSTRACT

Fırst discovered as a circulating secreted molecule expressed by activated T lymphocytes, attractin was examined as a potential marker of immune activity. The discovery that a transmembrane form not only controls neuropeptide regulation of hair pigmentation in animals but also affects basal metabolism led to proposals that attractin may also be an extracellular target amenable for the development of obesity-regulating drugs. Examination of several animal mutants used as models of juvenile-onset neurodegeneration revealed mutations at the attractin locus as the cause, and the reassessment of earlier attractin mutants demonstrated that neurodegeneration, alterations in pigmentation regulation, and basal metabolic rate were common to all the allelic variants. The presentation and severity of the symptoms differ depending upon the mutation, and some may be variably penetrant even within an allelic line. In this report, we review our rapidly altering perception of the functional activity of attractin with each further addition to its sphere of physiological involvement. We further reappraise our concepts of the subcellular location of attractin, leading to a new proposal that provides a unifying mechanism for attractin's pleiotropic activities. Progress in elucidating each new aspect of attractin function provides a case study in the evolution of possible therapeutic interventions as well as illuminating some of the pitfalls of studying molecular pathways isolated from the whole organism physiology.