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Degradation of Lung Adenoma Susceptibility 1, a Major Candidate Mouse Lung Tumor Modifier, Is Required for Cell Cycle Progression

Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Ming You, Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University, 660 Euclid Avenue, Box 8109, St. Louis, MO 63110. Phone: 314-362-9294; Fax: 314-362-9366; E-mail: youm{at}wustl.edu.

We have previously identified murine lung adenoma susceptibility 1 (Las1) as the pulmonary adenoma susceptibility 1 candidate gene. Las1 has two natural alleles, Las1-A/J and Las1-B6. Las1 encodes an 85-kDa protein with uncharacterized biological function. In the present study, we report that Las1 is an unstable protein and the rapid destruction of Las1 depends on the ubiquitin-proteasome pathway. Las1 is a new microtubule-binding protein and Las1 associated with tubulin is not ubiquitinated. We further show that Las1-A/J is a more stable protein than Las1-B6. Las1 is expressed in the G₂ phase of the cell cycle and that ubiquitin-proteasome–mediated Las1 destruction occurs in mitosis. Overexpression of Las1-A/J inhibits normal E10 cell proliferation and induces a defective cytokinesis. The differential degradation of Las1-A/J and Las-B6 has important implications for its intracellular function and may eventually explain Las1-A/J in lung tumorigenesis. [Cancer Res 2007;67(21):10207–13]