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c-Jun NH₂-Terminal Kinase 22 Promotes the Tumorigenicity of Human Glioblastoma Cells

¹ Department of Neurosurgery and ² Cancer Biology Program, Stanford University Medical Center, Stanford, California; and ³ Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Albert J. Wong, Department of Neurosurgery/Cancer Biology Program, Stanford University Medical Center, 300 Pasteur Drive, Edwards R221, Stanford, CA 94305-5327. Phone: 650-736-4220; Fax: 650-723-7813; E-mail: ajwong{at}stanford.edu.

c-Jun NH₂-terminal kinases (JNK) are members of the mitogen-activated protein kinase family and have been implicated in the formation of several human tumors, especially gliomas. We have previously shown that a 55 kDa JNK isoform is constitutively active in 86% of human brain tumors and then showed that it is specifically a JNK2 isoform and likely to be either JNK22 or JNK2ß2. Notably, we found that only JNK2 isoforms possess intrinsic autophosphorylation activity and that JNK22 has the strongest activity. In the present study, we have further explored the contribution of JNK2 isoforms to brain tumor formation. Analysis of mRNA expression by reverse transcription-PCR revealed that JNK22 is expressed in 91% (10 of 11) of glioblastoma tumors, whereas JNK2ß2 is found in only 27% (3 of 11) of tumors. Both JNK22 and JNK2ß2 mRNAs are expressed in normal brain (3 of 3). Using an antibody specific for JNK2 isoforms, we verified that JNK22 protein is expressed in 88.2% (15 of 17) of glioblastomas, but, interestingly, no JNK22 protein was found in six normal brain samples. To evaluate biological function, we transfected U87MG cells with green fluorescent protein–tagged versions of JNK11, JNK22, and JNK22APF (a dominant-negative mutant), and derived cell lines with stable expression. Each cell line was evaluated for various tumorigenic variables including cellular growth, soft agar colony formation, and tumor formation in athymic nude mice. In each assay, JNK22 was found to be the most effective in promoting that phenotype. To identify effectors specifically affected by JNK22, we analyzed gene expression. Gene profiling showed several genes whose expression was specifically up-regulated by JNK22 but down-regulated by JNK22APF, among which eukaryotic translation initiation factor 4E (eIF4E) shows the greatest change. Because AKT acts on eIF4E, we also examined AKT activation. Unexpectedly, we found that JNK22 could specifically activate AKT. Our data provides evidence that JNK22 is the major active JNK isoform and is involved in the promotion of proliferation and growth of human glioblastoma tumors through specific activation of AKT and overexpression of eIF4E. (Cancer Res 2006; 66(20): 10024-31)

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