(from the application): During cell division duplicated chromosomes are distributed equally into daughter cells- a process termed mitosis. The biochemical events that bring about mitosis in normal cells are ill defined. Our long-term objectives are to elucidate the signaling pathways that regulate spindle dynamics and chromsome segregation in normal cells. In addition, we are interested in determining whether errors in these pathways contribute to tumorigenesis. We will focus on the role of a particular signaling pathway at mitosis, the mitogen-activated protein kinase (MAPK) cascade. Our interest in MAP kinase was stimualted by our discovery that it is required for normal mitotic progression and for maintaining the dynamic properties of microtubules during mitosis in Xenopus egg extracts. This indicates a role for MAP kinase in the regulation of the mitotic spindle. The fact that MAP kinase associates with spindle poles, kinetichores and midbody during M phase in mammalian cells further suggests it plays multiple roles throughout mitosis. Mechanistically, little is known about how MAPK signaling is involved in mediating M-phase progression. We intend to exploit the Xenopus egg extract system to dissect how MAP kinase activation is regulated during mitosis. Furthermore, we will use biochemical and cellular approaches to determine the function of MAP kinase at mitosis in mammalian cells. We hypothesize that MAPK signaling at mitosis is critical for regulating the processes that coordinate spindle dynamics and chromosome segregation during cell division. To test this hypothesis, we propose three specific aims: 1. Define the cellular events of mitosis that are regulated by MAPK signaling in mammalian cells. 2. Determine the role MAPK plays in regulating the formation and function of the mitotic spindle apparatus. 3. Determine the biochemical steps that regulate MAPK activation during mitosis. In summary, we propose to elucidate the regulation and function of MAPK at mitosis in normal cells. Ultimately, we hope to establish whether defects in MAP kinase regulation during mitosis may contribute to genomic instabilities associated with tumor progression.
Showing the most recent 10 out of 30 publications
