? Maintenance of genetic integrity is essential for normal cells to ensure the error-free DNA replication and cell proliferation. In response to DNA damage agents, such as ionizing radiation, ultraviolet radiation and chemical compounds, a cellular mechanism is developed to protect the genetic integrity. This DNA damage signaling pathway is initiated by ATM kinase, a gene mutated in a rare genetic disease ataxia telangiectasia (AT). Activated ATM kinase leads to three major cellular events, cell cycle arrest, DNA damage repair and apoptosis. An immediate ATM downstream target, CHK2, plays a critical role in cell cycle checkpoint regulation and DNA damage induced apoptosis. CHK2 is a tumor suppressor and the germline mutation of CHK2 was found in a subset of familial genetic cancer syndrome, Li-Fraumeni Syndrome, in which p53 tumor suppressor is mutated in majority of the patients. We have detected the absence of CHK2 protein expression within the non-small cell lung cancer cell lines, and the absence of CHK2 protein expression is due to the absent expression of CHK2 mRNA. We have also demonstrated that under normal conditions, CHK2 is diminished in response to DNA damage agent cisplatin. We propose to determine the CHK2 expression levels in the tumor specimens from the lung cancer patients. We will study the molecular mechanism underlying the absence of CHK2 protein within the non-small cell lung cancer cell lines with particular emphasis of CHK2 promoter methylation and regulation of transcription. We will study the functional significance of re-introduction of CHK2 kinase into the lung cancer cells in relation to its sensitivity to DNA damage agents such as cisplatin and ionizing radiation. CHK2 null cells and the mice show remarkable resistance to DNA damage induced apoptosis, which bears significant similarity to clinical behavior of non-small cell lung cancer to DNA damage based therapy. The study of the molecular mechanism of the absent expression of CHK2 kinase in non-small cell lung cancer will not only greatly enhance the understanding of CHK2 function and cell cycle regulation, but also provide insight that potentially represent a new target for drug development for non-small cell lung cancer. ? ?
| Wiltshire, Timothy; Senft, Jamie; Wang, Yutian et al. (2007) BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven. Mol Pharmacol 71:1051-60 |
| Wang, Yutian; Wiltshire, Timothy; Senft, Jamie et al. (2007) Irofulven induces replication-dependent CHK2 activation related to p53 status. Biochem Pharmacol 73:469-80 |
| Wang, Yutian; Wiltshire, Timothy; Senft, Jamie et al. (2006) Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven. Mol Cancer Ther 5:3153-61 |
