Dissertaties - Rijksuniversiteit Groningen
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The mitotic checkpoint: mechanism and biological relevance

(2008) Jeganathan, Karthik Babu

Most human cancers have an aberrant number of chromosomes but whether aneuploidy plays a causal role in tumor formation or is a merely a feature of cancerous cells has become one of the classical questions in cancer biology. Other important questions in this field relate to the identity, functions and physiological relevance of the genes implicated in chromosome segregation in mitosis. Studies described in this thesis were directed toward addressing these questions.
Our studies focused on two classes of mitotic regulators. A first class includes proteins normally associated with transport across the nuclear envelope through nuclear pores. Their role in chromosome stability is a novel function for these proteins. Two members of this class of proteins that we studied in greater detail are the mRNA export factor Rae1 and the nuclear pore complex protein Nup98. Using mutant mice and MEFs with low amounts of Rae1 and Nup98, we discovered that, at the onset of mitosis, these two transport factors form a complex with Cdh1 and APC/C to prevent unscheduled APC/CCdh1-mediated degradation of the anaphase inhibitor securin, thereby preventing premature sister chromosome separation, chromosome missegregation, aneuploidy and tumor formation. The second class of mitotic regulators that we studied consists of core components of the mitotic checkpoint, a molecular network that ensures proper separation of duplicated chromosomes by preventing anaphase onset until all kinetochores have attached to spindle microtubules. We focused our studies on two related mitotic checkpoint proteins with serine/threonine kinase activity, Bub1 and BubR1. To study their physiological relevance we had to use hypomorphic mouse strains that express low levels of these proteins, because Bub1 and BubR1 are both essential proteins. A very surprising finding was that mice with low amounts of BubR1 age 4-5 times faster than normal mice. This combined with the observation that BubR1 levels decline in various mouse tissues with age, led us to propose that BubR1 is a regulator of natural aging. Although BubR1 mice develop severe aneuploidy, this abnormality does not seem to drive accelerated aging. Even though Bub1 is closely related to BubR1, Bub1 hypomorphic mice do not age prematurely. Instead, Bub1 plays a very prominent role in tumor suppression. We show that Bub1 is unique in the sense that it not only prevents chromosome missegregation by inhibiting anaphase onset until all chromosomes are properly attached to the mitotic spindle, but also mediates cell death in the event chromosome missegregation does occur. We speculate that because of this dual role, Bub1 deficiency allows for formation of a much broader spectrum of abnormal karyotypes than other mitotic checkpoint protein defects, thereby increasing the likelihood that malignant karyotypes evolve.

file:Title and contents-Chapter 1
file:Chapter 2
file:Chapter 3 - Chapter 4
file:Chapter 5
file:Chapter 6 [p.105-108]
file:Chapter 6 [p.109-122]
file:Chapter 7 [Page 123-127]
file:Chapter 7 [Page 128-140]
file:Chapter 8; Chapter 9; Summary; Samenvatting; Acknowledgements; Publications; Curriculum Vitae

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