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Nitta RT, Del Vecchio CA, Chu AH, Mitra SS, Godwin AK, Wong AJ
The role of the c-Jun N-terminal kinase 2-alpha-isoform in non-small cell lung carcinoma tumorigenesis
Oncogene (2011) 30:234-244.
The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family and have been implicated in tumorigenesis. One isoform in particular, JNK2 alpha, has been shown to be frequently activated in primary brain tumors, to enhance several tumorigenic phenotypes and to increase tumor formation in mice. As JNK is frequently activated in non-small cell lung carcinoma (NSCLC), we investigated the role of the JNK2 alpha isoform in NSCLC formation by examining its expression in primary tumors and by modulating its expression in cultured cell lines. We discovered that 60% of the tested primary NSCLC tumors had three-fold higher JNK2 protein and two-to three-fold higher JNK2 alpha mRNA expression than normal lung control tissue. To determine the importance of JNK2 alpha in NSCLC progression, we reduced JNK2 alpha expression in multiple NSCLC cell lines using short hairpin RNA. Cell lines deficient in JNK2 alpha had decreased cellular growth and anchorage-independent growth, and the tumors were four-fold smaller in mass. To elucidate the mechanism by which JNK2 alpha induces NSCLC growth, we analyzed the JNK substrate, signal transducer and activator of transcription 3 (STAT3). Our data demonstrates for the first time that JNK2 alpha can regulate the transcriptional activity of STAT3 by phosphorylating the Ser727 residue, thereby regulating the expression of oncogenic genes, such as c-Myc. Furthermore, reintroduction of JNK2 alpha 2 or STAT3 restored the tumorigenicity of the NSCLC cells, demonstrating that JNK2 alpha is important for NSCLC progression. Our studies reveal a novel mechanism in which phosphorylation of STAT3 is mediated by a constitutively active JNK2 isoform, JNK2 alpha. Oncogene (2011) 30, 234-244; doi: 10.1038/onc.2010.414; published online 27 September 2010
Publication Date: 2011-01-01.
Last updated on Monday, July 06, 2020