RT Journal Article
SR Electronic
T1 Constitutive Activation of Mitogen-activated Protein (MAP) Kinases in Human Renal Cell Carcinoma
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4182
OP 4187
VO 55
IS 18
A1 Oka, Hiroya
A1 Chatani, Yuji
A1 Hoshino, Rika
A1 Ogawa, Osamu
A1 Kakehi, Yoshiyuki
A1 Terachi, Toshiro
A1 Okada, Yusaku
A1 Kawaichi, Masashi
A1 Kohno, Michiaki
A1 Yoshida, Osamu
YR 1995
UL http://cancerres.aacrjournals.org/content/55/18/4182.abstract
AB 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. ©1995 American Association for Cancer Research.