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Constitutive Activation of Mitogen-activated Protein (MAP) Kinases in Human Renal Cell Carcinoma¹

Department of Urology, Faculty of Medicine, Kyoto University, Kawahara-cho 54, Sakyo-ku, Kyoto 606 [H. O., O. O., Y. K., T. T., Y. O., O. Y.]; Department of Biology, Gifu Pharmaceutical University, Mitahora-higashi, Gifu 502 [Y. C., R. H., M. Ko.]; and Division of Gene Function in Animals, Nara Institute of Science and Technology, Takayama-cho 8916-5, Ikoma, Nara 630-01 [M. Ka.], Japan

Mitogen-activated protein kinases (MAPKs) play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAPK cascade, which includes MEK (also known as MAP kinase kinase), Raf-1, and Ras. In this study, we examined whether constitutive activation of the MAPK cascade was associated with the carcinogenesis of human renal cell carcinomas in a series of 25 tumors and in corresponding normal kidneys. Constitutive activation of MAPKs in tumor tissue, as determined by the appearance of phosphorylated forms, was found in 12 cases (48%), and this activation was confirmed by a direct in vitro kinase assay of immunoprecipitate using myelin basic protein as the substrate. The phosphorylation of MEK and of Raf-1, as monitored by a mobility shift in SDS-PAGE, which is reportedly associated with the activation of these kinases, occurred in 9 of 18 cases (50%) and in 6 of 11 cases (55%) respectively. The activation of MAPKs was correlated with MEK activation (P = 0.0045) and with Raf-1 activation (P = 0.067). Furthermore, overexpression of MEK was found in 13 of 25 cases (52%) by Western blot analysis, and this overexpression was associated significantly with MAPK activation (P = 0.034). No mutations were noted in H-,K-, or N-ras genes by PCR direct sequencing in any of the 25 tumor samples. Of the patients studied, 8 of 18 (44%) stage pT₂ patients and four of six (67%) stage pT₃ patients showed MAPK activation. The single stage pT₁ patient did not evidence MAPK activation. Furthermore, one of seven (14%) grade 1 patients, 9 of 13 (69%) grade 2 patients, and two of five (40%) grade 3 patients showed MAPK activation (grade 1 versus grades 2 and 3, P = 0.046). Our results suggest that constitutive activation of MAPKs may be associated with the carcinogenesis of human RCCs.

¹ This work was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture of Japan.

² To whom requests for reprints should be addressed.

Received 5/ 1/95. Accepted 7/19/95.

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