Mitotic spindle checkpoint

In contrast to the DNA damage checkpoint, the mitotic spindle checkpoint is essential for cell viability. Dierefore, targeting kinases of the spindle checkpoint including Bubl, BubRl, and Mpsl might be a valid strategy for anticancer treatment. 

Activation of p53 can bring about a halt in the cell cycle at the important cell cycle transitions. Thus, the p53 protein is involved in the control of the Gl/S transition, the mitotic spindle checkpoint and the G2/M transition. There is increasing experimental evidence that the halt is irreversible and that the cell can survive for a very long time in this resting state. 

Masuda A, Maeno K, Nakagawa T et al. Association between mitotic spindle checkpoint impairment and susceptibility to the induction of apoptosis by anti-microtubule agents in human lung cancers. Am... 

Kasai T, Iwanaga Y, Iha H et al. Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors. JBiol Chem 2002 277 5187-5193. 

Vogel C, Kienitz A, Muller R et al. The mitotic spindle checkpoint is a critical determinant for topoisomerase-based chemotherapy. J Biol Chem 2005 280 4025M028. 

Iwanaga Y, Jeang KT. Expression of mitotic spindle checkpoint protein hsMADl correlates with cellular proliferation and is activated by a gain-of-function p53 mutant. Cancer Res 2002 62 2618-2624. 

Rg. 17.1 The mitotic-spindle checkpoints ensure that chromosomes are aligried correctly before anaphase. If chromosomes are not attached stably to the microtubules, the checkpoint control prevents entry into anaphase, the irreversible step in cell division. ... 

Genes identified in the benomyl screens were named mad, for mitotic arrest deficient, or bub, for budding uninhibited by benomyl. The existence of these genes provided evidence for a feedback mechanism that delays anaphase onset until completion of spindle assembly, now often referred to as the mitotic spindle checkpoint. Much of our understanding of mitotic checkpoint signaling has developed from the mad and bub... 

Another class of substrates comprises the anaphase inhibitors, e. g., the protein securin. Securin is an inhibitor of a protease named separase, which cleaves proteins responsible for sister chromatid cohesion in metaphase. Destruction of these inhibitors is necessary for triggering of sister chromatid separation and progression into anaphase. Because of its central function, the APC is part of several cell cycle checkpoints, e. g., a DNA damage checkpoint and the mitotic spindle checkpoint. 

EXAMPLE 8.9 There are a number of checkpoints in the cell cycle. Gj has a checkpoint that prevents progression into M phase unless replication of all chromosomal DNA is complete. The M phase checkpoint ensures that the chromosomes have been correctly attached to the mitotic spindle. Checkpoints in the G, and S phases lead to arrest of the cell cycle if damaged DNA is detected by the relevant protein complex. 

A corollary to the mechanisms of cell-death execution is that a dying cell does not need to reach a stable apoptotic state to be dead. This creates a logistical problem for many standard dynamical-systems approaches (nullclines, bifurcation analysis, etc.) that are based on steady-state solutions to the governing equations. Aldridge and coworkers applied finite-time approaches (that do not require d/df = 0) to define the separation of cellular trajectories in a model of caspase activation (Aldridge et al. 2006). These types of approaches may be particularly relevant for other irreversible cell-fate choices, such as during the mitotic-spindle checkpoint. 

Kubiak In mouse, there is a weak checkpoint in meiosis for spindle formation. There are some responses where if the spindle is destroyed, the passage from metaphase I to metaphase II is blocked. There is other evidence that there is no checkpoint. I think there is a special checkpoint in meiosis. Starting from the first mitotic division there is no spindle checkpoint. 

Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 2003 3 51-62. 

In telophase, nuclei for each daughter cell form at the two poles, and the mitotic spindle apparatus disappears. Furthermore, nuclear membranes, nuclear lamina, nuclear pores, and nucleoli are reformed. The cell is now ready for cytokinesis, which is physical division of the cytoplasm. The cytoplasm divides as actin/myosin filaments contract and pinch off the plasma membrane, which results in two daughter cells that enter into Go or Gi for another round of division. The main checkpoint that exists during M phase in mammalian cells is the spindle checkpoint it is in place to ensure proper microtubule assembly, proper cell division, and that each daughter cell receives one copy of DNA. 

Benomyl was used in the mad and bub screens not because of its specific protein target but because of the perturbation of spindle assembly. In principle, the same experiments could have been done without knowing the protein target or by targeting a different component of the spindle. The generality of the spindle checkpoint has been demonstrated through the use of monastrol, a small-molecule inhibitor of the mitotic kinesin Eg5, which was identified in a screen for small molecules that arrest cells in mitosis without targeting tubulin (24). Monastrol treatment arrests cells in mitosis with monopolar spindles because Eg5 is required to separate the spindle poles. The inhibition of... 

Inhibitors of Eg5 are currently in development as anticancer drugs because, like taxol and the vinca alkaloids, they arrest cells in mitosis by activating the spindle checkpoint. The efficacy of these drugs, as demonstrated by recent studies, requires a prolonged, checkpoint-dependent mitotic arrest [42, 19]. Drug resistance is conferred by a compromised spindle checkpoint, for example, through reduced expression of Mad2. 

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