PARENT SESSION
9:00 AM to 11:00 AM
Tuesday, April 23, 2002
Symposium 17
Mouse Models of Disease
Room: Nevada 1-2
Chair: Lieberman, Howard²²Columbia Univ., NY, NY, Co-Chair: Fornace, Albert³³37/6144, Bethesda, MD
Speakers: Wynshaw-Boris, Tony⁴; Li, Gloria⁵; Lieberman, Howard⁶; Fornace, Albert⁷⁴University of California, San Diego Sch. of Medicine, La Jolla, CA⁵Dept. of Medical Physics, NY, NY⁶630 W 168th St, NY, NY⁷37/6144, Bethesda, MD

(S17-1) Atm mutant mice as a model of ataxia-telangiectasia.

Wynshaw-Boris, Anthony^*,1, ¹ UCSD School of Medicine, La Jolla, CA

ABSTRACT-
Ataxia-telangiectasia (AT) is a pleiotropic and devastating human autosomal recessive disorder that results in death within the first few decades of life primarily from progressive neurologic deterioration and/or malignancy, particularly lymphoreticular cancers. In addition, humans with AT display telangiectasias (dilated blood vessels of the conjunctiva and skin), growth retardation, variable immune difficiency, infertility and sensitivity to ionizing radiation. Heterozygous carriers may have an increased predisposition to cancer, particularly breast cancer. The protein product of the gene mutated in AT, ATM, is a member of a large family of kinases that is conserved throughout eukaryotic evolution. ATM is a central regualtory kinase that acts in mitotic, post-mitotic and meiotic cell types in the body, and is essential for diverse pathways such as cell cycle checkpoints, DNA damage responses, stress responses, and perhaps membrane trafficking. In particular, ATM phosphorylates proteins involved in the G1/S phase (p53), S phase (NBS1) and G2/M (CHK2) checkpoints. My laboratory has produced and studied a mouse model of AT by inactivating the murine Atm gene using targeted mutagenesis. This mouse model recapitulates the pleiotropic AT syndrome in humans. We have used these mice to study in the whole animal the genetic and biochemical pathways regulated by ATM and the dyregulation of these pathways in the absence of ATM. We have discovered tissue-specific differences in the biochemical responses to loss-of-function of ATM, and provided evidence that distinct Atm-dependent pathways in different tissues may be responsible for the pleiotropic phenotype of Atm-deficient mice.

KEYWORDS: Ataxia-telangiectasia, Mouse model