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Review
. 2008 Jun 2;181(5):719-26.
doi: 10.1083/jcb.200802107.

Original CIN: reviewing roles for APC in chromosome instability

Nasser M Rusan  1 , Mark Peifer
Affiliations
Review

Original CIN: reviewing roles for APC in chromosome instability

Nasser M Rusan et al. J Cell Biol. .

Abstract

You may have seen the bumper sticker "Eve was framed." Thousands of years of being blamed for original sin and still many wonder, where's the evidence? Today, the tumor suppressor adenomatous polyposis coli (APC) may have the same complaint about accusations of a different type of CIN, chromosome instability. A series of recent papers, including three in this journal, propose that loss of APC function plays an important role in the CIN seen in many colon cancer cells. However, a closer look reveals a complex story that raises more questions than answers.

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Figures

Figure 1.
Figure 1.
APC localization. APC has been localized to several subcellular locations, some of which are highlighted here.
Figure 2.
Figure 2.
Models suggesting APC modulates the SAC or its response to attachment defects. (A) Proposed pathway in wild-type cells. APC promotes stable MT–kinetochore attachment through an unknown mechanism. The SAC monitors MT–kinetochore attachment and only allows mitotic exit once MT occupancy and tension are satisfactory. (a) In Sorger's model (Draviam et al., 2006), SAC function does not require APC. (b) In Näthke's model (Dikovskaya et al., 2007), APC plays a direct role in SAC function. (B) Proposed model accounting for chromosome segregation defects in the absence of APC. Disruption of APC seems to lead to defects in MT–kinetochore attachment, but models differ in what happens downstream. (a) In Sorger's model (Draviam et al., 2006), a functional SAC prolongs metaphase to attempt to correct attachment defects, but some defects remain undetected/uncorrected. This leads to mitotic exit of cells with lagging chromosomes, leading to aneuploidy. (b) In Näthke's model (Dikovskaya et al., 2007), defects in APC lead to compromised SAC function. This leads to mitotic exit without chromosome segregation, generating tetraploid cells.
Figure 3.
Figure 3.
Models suggesting roles for APC in MT–kinetochore attachment. (A) Wild-type MT attachment at the end of metaphase, when MT number is balanced and interkinetochore distance is normal. (B) In APC mutant cells, interkinetochore distance is reduced, which could be a result of several different defects in MT attachment. (C) A model in which these defects lead to lagging chromosomes and aneuploidy. (D) A model in which these defects and defects in the SAC lead to mitotic exit without cytokinesis and tetraploidy.
Figure 4.
Figure 4.
Model suggesting APC regulates astral MT formation and thus cytokinesis. Cells depleted of APC sometimes have reduced astral MT arrays. This could trigger failed cytokinesis given the known role of astral MTs in defining and initiating formation of the cytokinetic furrow.
Figure 5.
Figure 5.
The current model for APC function in Wnt signaling. (A) Functional APC assists in phosphorylating and targeting β-catenin for destruction. (B) Loss of APC leads to accumulation of β-catenin and, thus, transcription of Wnt-responsive genes.
See this image and copyright information in PMC

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