Checkpoint mitotic

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

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. 

Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H 1997 Mitotic and G2 checkpoint control regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277 1501—1505... 

Cahill DP, Lengauer C, Yu J et al 1998 Mutations of mitotic checkpoint genes in human cancers. Nature 392 300-303... 

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. 

The cell cycle is a key process that recurs in a periodic manner. Early cell cycles in amphibian embryos are driven by a mitotic oscillator. This oscillator produces the repetitive activation of the cyclin-dependent kinase cdkl, also known as cdc2 [131]. Cyclin synthesis is sufficient to drive repetitive cell division cycles in amphibian embryonic cells [132]. The period of these relatively simple cell cycles is of the order of 30 min. In somatic cells the cell cycle becomes longer, with durations of up to 24 h or more, owing to the presence of checkpoints that ensure that a cell cycle phase is properly completed before the cell progresses to the next phase. The cell cycle goes successively through the phases Gl, S (DNA replication), G2, and M (mitosis) before a new cycle starts in Gl. After mitosis cells can also enter a quiescent phase GO, from which they enter Gl under mitogenic stimulation. 

Taylor S S, McKeon F. Kinetochore localization of murine B ub 1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 1997 89(5) 727-735. 

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. 

DNA Repair and Mitotic Checkpoint Genes as Potential Predictors of Chemotherapy Response in Non-Small-Cell Lung Cancer... 

The same premises of customization can be applied to early NSCLC. Various clini-eal observations indieate that when these defense NER genes are overexpressed in re-seeted NSCLCs, they reflect a lower risk of relapse and increased cisplatin resistance. Several layers of evidence show that BRCAl can be the most important predictive marker for eustomizing chemotherapy. In addition, the clinical value of several mitotic checkpoint genes that are dysfunctional in NSCLC and regulated by BRCAl should also be investigated. 

Fig. 2. BRCAl involved in regulation of mitotic checkpoint genes. (Reprinted with permission from Mullan et al. BRCAl A good predictive marker of drug sensitivity in breast cancer treatment Biochim Biophys Acta, in press,with kind permission from Elsevier).

Preclinical evidence indicates that knockdown of BRCAl by small interference RNA (siRNA) in T47D cells leads to a 50-fold increase in resistance to paclitaxel. The increased sensitivity to paclitaxel observed in BRCAl reconstituted cells correlated with the activation of the mitotic checkpoint and an increase in apoptosis (40,55). 

Destruction of cohesin allows the spindle microtubules to pull the separated chromatids to opposite poles of the cell. Failure of spindle attachment to a single kinetochore activates the SAC (spindle assembly checkpoint), which arrests cells at metaphase until corrections are effected and equal distribution of chromosomes has been ensured. A sensory mechanism initiates the wait anaphase signal from an imattached kinetochore and triggers the accu mulation of the checkpoint components that comprise the Bub (budding uninhibited by benomyl)-Mad (mitotic arrest deficient) families of proteins. 

Fig. 4. A graphic representation of the phases of mitosis and the key mitotic checkpoints involved. (Reprinted with permission from Baker DJ, Chen J, van Deursen JMA. The mitotic checkpoint in cancer and aging what have mice taught us Curr Opin Cell Biol 2005 17 583-589, with kind permission from Elsevier).

Mitotic checkpoint defects have been found in many human cancers (72,73,74,75,76). While Mad2 gene mutations occur rarely in many kinds of cancer (74,77), aberrant reduction of Mad2 is often observed (72,74,78). The T47D breast cancer cell line that is sensitive to paclitaxel and nocodazole had reduced Mad2 expression and failed to arrest in mitosis after nocodazole treatment (72). 

Mitotic Checkpoint Defects in Cancer Cell Lines and Chemotherapy Sensitivity... 

Baker DJ, Chen J, van Deursen JM. The mitotic checkpoint in cancer and aging what have mice taught us Curr Opin Cell Biol 2005 17 583-589. 

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