Oncogene
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Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL genetic translocation and constitutive activation of the Abl tyrosine kinase. Among members of the Signal Transducers and Activators of Transcription (STAT) family of transcription factors, Stat5 is activated by the Bcr-Abl kinase and is implicated in the pathogenesis of CML. We recently identified PD180970 as a new and highly potent inhibitor of Bcr-Abl kinase. ⋯ To detect activated Stat5 in CML patient specimens, we developed an immunocytochemical assay that can be used as a molecular end-point assay to monitor inhibition of Bcr-Abl signaling. Moreover, PD180970 blocked Stat5 signaling and induced apoptosis of STI-571 (Gleevec, Imatinib)-resistant Bcr-Abl-positive cells. Together, these results suggest that the mechanism of action of PD180970 involves inhibition of Bcr-Abl-mediated Stat5 signaling and provide further evidence that compounds in this structural class may represent potential therapeutic agents for CML.
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Erb-B-3 overexpression is associated with poor prognosis in non-small cell lung cancer and is often overexpressed in breast cancers. MMTVhuman-erb-B-3 transgenic mice were generated to evaluate the impact of erb-B-3 overexpression on lung and mammary gland tumorigenesis. These transgenic mice developed a high incidence of lung adenocarcinomas but not mammary gland tumors. ⋯ Coupled erb-B-2 and erb-B-3 overexpression as well as K-ras activation induced signaling through mitogen-activated protein kinase (MAPK). This animal model links erb-B-3 with lung cancer, suggests that erb-B-2 and erb-B-3 heterodimerization is a necessary intermediate, and documents latency shortening by methylating agent-induced mutation of K-ras. This erb-B-3 mouse lung cancer model will help dissect genetic changes in lung tumorigenesis and may be useful for chemoprevention studies.