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Review
. 2000 Oct;33(5):261-74.
doi: 10.1046/j.1365-2184.2000.00191.x.

Cell cycle checkpoints and their inactivation in human cancer

M Molinari  1
Affiliations
Review

Cell cycle checkpoints and their inactivation in human cancer

M Molinari. Cell Prolif. 2000 Oct.

Abstract

Checkpoints are mechanisms that regulate progression through the cell cycle insuring that each step takes place only once and in the right sequence. Mutations of checkpoint proteins are frequent in all types of cancer as defects in cell cycle control can lead to genetic instability. This review will focus on three major areas of cell cycle transition control, with particular attention to the alterations found in human cancer. These areas include the G1/S transition, where most cancer-related defects occur, the G2/M checkpoint and its activation in response to DNA damage, and the spindle checkpoint.

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Figures

Figure 1
Figure 1
The G1/S transition in mammalian cells. CycD is a sensor of mitogenic stimuli linking the cell cycle with the external environment. Growth factor‐induced cycD accumulation results in the formation of active cycD/cdk4, which overcomes inhibition by p16 and phosphorylates Rb. This crucial event marks the transition through the restriction point (R) and induces the release of E2F transcriptional repression mediated by the HDAC protein, with the consequent transactivation of genes necessary for S phase initiation and progression. The targets of mutations found in human cancer are hatched in the Figure; alterations include Rb mutations or deletions, HDAC mutations, cycD overexpression, p16 mutations, cdk4 mutations, increased degradation of p27.
Figure 2
Figure 2
Regulation of the G2/M transition. Entry into mitosis depends on the activation of the cdc2/cycB complex and its subcellular localization. Cyc B is cytoplasmic until G2, when the rate of import exceeds nuclear export. The wee1 and myt1 protein kinases phosphorylate and inactivate the nuclear and cytoplasmic pool of cdc2/cycB, respectively, preventing premature mitotic entry. Accumulation and activation of cdc25B in G2 brings about the initial activation of cdc2/cycB. Cdc25C shuttles between the nucleus and the cytoplasm throughout interphase, with a net cytoplasmic localization. In G2 it accumulates in the nucleus and mediates further activation of cdc2/cycB, which in turn activates it, forming an autocatalytic loop that results in entry into mitosis.
Figure 3
Figure 3
Regulation of the G2/M transition. DNA damage inhibits G2/M progression via two mechanisms. Upon DNA damage the p53 protein is stabilized and activated as a transcription factor. One of its targets is the 14‐3‐3 σ gene, which mediates the sequestration of cdc2/cycB in the cytoplasm. DNA damage also induces the activation of the Chk1/Chk2 protein kinases through an ATM‐dependent mechanism. Chk1/Chk2‐dependent phosphorylation of Cdc25C induces its binding to 14‐3‐3 proteins which inactivate it by sequestering it in the cytoplasm.
Figure 4
Figure 4
The spindle checkpoint. Proper chromosome alignment in metaphase and microtubule attachment to the kinetochores induces the activation of APC, which mediates the degradation of proteins acting as a ‘molecular glue’ to hold together sister chromatids, thus allowing sister chromosomes separation. Defects in microtubule attachment result in activation of the Mad and Bub proteins, that phosphorylate the regulatory subunit of APC inhibiting its activity, with the result of preventing metaphase‐anaphase transition. Loss of function of these sensor proteins results in chromosome segregation even in conditions of a defective spindle, leading to aneuploidy.
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