In the presence of misaligned chromosomes, normal somatic cells arrest in M phase. This surveillance system or cell cycle checkpoint prevents the generation of progeny cells with too many or too few chromosomes. The long-term objective of this work proposed here application is delineating all steps of the signaling pathways that regulate mitotic cell cycle checkpoints. The working hypothesis is that signals blocking the onset of anaphase emanate from """"""""relaxed"""""""" kinetochores, those lacking stable microtubule attachments. Mechanical tension imparted by the attachment of mitotic spindle microtubules leads to conformational changes of in kinetochore components and turns off the checkpoint signal. The checkpoint signal at the kinetochore involves protein phosphorylation recognized by the 3F3/2 monoclonal antibody.
The specific aims of this proposal are: dissecting the molecular nature of the 3F3/2 phosphoepitope, and determining how it participates in checkpoint regulation, identifying the kinase that creates the 3F3/2 phosphoepitope and determining how it is regulated during the cell cycle, and lastly determining how kinase activity is regulated by tension. M phase checkpoints play an essential role in assuring equal segregation of chromosomes in mitosis and meiosis. In cancer, cell cycle checkpoints are often faulty. In some instances this may, in fact, potentiate the induction of apoptosis by tumor therapies. However, chromosome imbalances also contribute to the progression of malignancy in tumors. In germ cell maturation, chromosomal imbalances induced during meiosis are a significant cause of birth defects. Understanding how the M phase checkpoints are regulated promises new ways of understanding and novel avenues for intervention in human cancer and birth defects.
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