Mitogen-activated protein (MAP) kinase pathways are three-kinase modules that mediate diverse cellular processes and have been highly conserved among eukaryotes. By using a functional complementation screen in yeast, we have identified a human MAP kinase kinase kinase (MAPKKK) that shares homology with members of the mixed lineage kinase (MLK) family and therefore was called MRK (MLK-related kinase). We report the structure of the MRK gene, from which are generated two splice forms of MRK, MRK-␣ and MRK-, encoding for proteins of 800 and 456 amino acids, respectively. By using a combination of solid phase protein kinase assays, transient transfections in cells, and analysis of endogenous proteins in stably transfected Madin-Darby canine kidney cells, we found that MRK- preferentially activates ERK6/p38␥ via MKK3/MKK6 and JNK through MKK4/MKK7. We also show that expression of wild type MRK increases the cell population in the G 2 /M phase of the cell cycle, whereas dominant negative MRK attenuates the G 2 arrest caused by ␥-radiation. In addition, exposure of cells to ␥-radiation induces MRK activity. These data suggest that MRK may mediate ␥-radiation signaling leading to cell cycle arrest and that MRK activity is necessary for the cell cycle checkpoint regulation in cells.
The growth factor independence-1 (Gfi1) transcription factor is required for proper development of neuroendocrine cells, sensory neurons, and blood. Patients with mutations in Gfi1 exhibit severe congenital neutropenia (SCN) or non-immune chronic idiopathic neutropenia of adults. Gfi1 was initially described as an oncoprotein that mediates tumor progression in a mouse model of leukemia; however, recent data suggest that Gfi1 may act as either an oncogene or an anti-proliferative tumor suppressor gene depending on the cell type. Here we review the latest literature on Gfi1, and emphasize its role in the hematopoietic, sensory and neuroendocrine systems.
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