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Reduced Expression and Impaired Kinase Activity of a Chk2 Mutant Identified in Human Lung Cancer¹

Howard Hughes Medical Institute, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 [S. M., S. J. E.], and Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan [T. N., A. M., N. H., T. T.]

The checkpoint kinase Chk2 is phosphorylated and activated in response to DNA damage such as ionizing radiation. Recently, we found a somatic mutation of CHK2 with clear loss of the wild-type allele in human lung cancer. Here we show that the mutant Chk2 exhibits modestly reduced in vitro kinase activity compared with wild type, whereas it is normally phosphorylated and activated after ionizing radiation. Interestingly, this mutant Chk2 protein was found to be less stable than wild type and could be expressed in various cell types only at a significantly reduced (20%) level of wild type. These findings confirm that the DNA damage checkpoint pathway involving CHK2 is indeed inactivated in this fatal adult cancer and also suggest that reduced expression of Chk2 may also be an important inactivating mechanism, contributing to the development of lung cancer.

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