Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17

The introduction of a discontinuous similar to 70-cM portion of human chrom osome 17 significantly suppresses the metastatic ability of AT6.1 rat prost ate cancer cells without affecting tumorigenicity (M, A. Chekmareva et at, Prostate, 33: 271-280, 1997), We have recently demonstrated that AT6.1 cell s containing the similar to 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the m etastasis suppressor region is Lost (M, A. Chekmareva et at, Cancer Res., 5 8: 4963-4969, 1998), A series of in vivo studies indicated that the observe d growth inhibition was due to the effect of a gene(s) at the metastatic si te (M,A, Chekmareva et at, Cancer Res., 58: 4963-4969, 1998), We have now i dentified the mitogen-activated protein kinase kinase 4/stress-activated pr otein/Erk kinase 1 (MKK4/SEK1) gene as a candidate metastasis suppressor ge ne encoded by the similar to 70-cM region. AT6.1 cells were transfected wit h a MKK4/SEK1 expression construct, and the cells were tested in standard s pontaneous metastasis assays, Whereas the metastatic ability of the AT6.1-M KK4/SEK1 cells was significantly reduced as compared with that of transfect ion controls, the growth rate of the primary tumors was not affected; the a verage tumor volume at day 29 after injection was similar to 2 cm, Furtherm ore, histological examination of the Lungs of AT6.1-MKK4/SEK1 tumor-bearing animals revealed that the suppression by MKK4/SEK1 is due to an effect at the metastatic site, consistent with the phenotype conferred by the origina l similar to 70-cM chromosomal region. These studies implicate MKK4/SEK1 as a metastasis suppressor gene encoded by human chromosome 17.