Roles of mob proteins in mitotic exit

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The separation of a cell into two daughter cells by cytokinesis must be tightly coordinated with the separation of the chromosomes into each of the daughters. In organisms with an open mitosis, where the nuclear envelope is disassembled and reassembled each time the cell divides, it is equally important that nuclear envelope assembly is coordinated with chromosome separation. In the budding yeast, Sacchromyces cerevisiae, the mitotic exit network (MEN) coordinates cytokinesis with chromosome segregation. Mob1 is an essential protein in the MEN and mutants in Mob1 fail to exit mitosis. Mob-related proteins, whose functions are unknown, are encoded by the genomes of all multicellular organisms, with humans having at least six separate genes for Mob proteins. We have begun the characterization of one of the human Mob proteins and have found that it is localized to the spindle poles and spindle midzone during mitosis. Depletion of this Mob protein results in a failure to complete mitosis, as judged by the incomplete assembly of the nuclear envelope. Moreover, the relocation of a chromosomal protein called aurora B is altered in Mob depleted cells, as it is in yeast Mob1 mutants. The effects of Mob depletion in human cells are similar to the effects of Mob1 mutations in yeast. This proposal is aimed at further characterizing the role of Mob proteins in mitotic exit. We will determine whether this or other Mob proteins are required for cytokinesis. We will examine whether other chromosomal or spindle proteins are affected when Mob is depleted, and whether the effects of Mob depletion are on a cell cycle progression or directly on nuclear envelope assembly. We will also attempt to identify proteins that interact with Mob in multicellular organisms. It is anticipated that these experiments will provide basic information on the control of cell division in all organisms.