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Molecular Biology and Genetics |
Sealy Center for Oncology and Hematology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555
Oncogenic (activated) Ras is a signal transducer that activates multiple effector-mediated signaling pathways leading to altered cell morphology, growth and differentiation, and neoplastic transformation. Activating mutations of Ras family genes have been detected in many types of human cancers, including lung cancer. However, the signaling mechanisms by which oncogenic Ras controls cancer cell growth is poorly characterized. This study evaluates the role of two specific signaling pathways, the c-Jun NH2-terminal kinase (JNK) pathway, and the extracellular signal-regulated kinase (ERK) pathway, in oncogenic Ras-induced morphological transformation of NCI-H82 human small cell lung cancer cells. In the NCI-H82 cell line, oncogenic Ras causes a marked and sustained activation of JNK but only has a modest effect on activation of the ERK pathway. The persistent JNK activation is associated with Ras-induced changes in cell morphology and enhanced transforming activity. Furthermore, JNK activation correlates with the induction of c-Jun expression, c-Jun phosphorylation on serines 63 and 73, and increased AP-1 activity. Deregulation of the JNK pathway using a dominant-negative mutant of JNK1, JNK1(APF), completely reverses the oncogenic Ras-induced transformed phenotype, including morphological reversion and inhibition of anchorage-independent growth and low-serum growth. Moreover, expression of JNK1(APF) leads to a decrease in c-Jun/AP-1 activity. In contrast, inhibition of ERK activation via a pharmacological approach using a mitogen-activated protein kinase/ERK kinase-specific inhibitor 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one is unable to reverse the Ras-induced transformed morphology and c-Jun/AP-1 induction. These results demonstrate that the JNK/c-Jun/AP-1 pathway plays an essential role in mediating oncogenic Ras function in lung carcinoma cells.
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