HUMAN MITOGEN-ACTIVATED PROTEIN-KINASE KINASE-4 AS A CANDIDATE TUMOR-SUPPRESSOR

Mitogen-activated protein kinases function in signal transduction path ways that are involved in controlling key cellular processes in many o rganisms. A mammalian member of this kinase family, MKK4/JNRK1/SEK1, h as been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase, This mi togen-activated protein kinase pathway has been implicated in the sign al transduction of cytokine-and stress-induced apoptosis in a variety of cell types, Here, we report that two human tumor cell lines, derive d from pancreatic carcinoma and lung carcinoma, harbor homozygous dele tions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 h uman cancer cell lines prescreened for loss of heterozygosity, we dete cted two nonsense and three missense sequence variants of MKK4 in canc er cell lines derived from human pancreatic, breast, colon, and testis cells, In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to ph osphorylate stress-activated protein kinase. Thus, the incidence of co ding mutations of MKK4 in the set of cell lines is 6 of 213 (similar t o 3%). These findings suggest that MKK4 may function as a suppressor o f tumorigenesis or metastasis in certain types of cells.