Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis

Abstract

v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth suppression and apoptosis. In this review, we highlight recent progress in our understanding of cytokinesis failure and the attenuation of the tetraploidy checkpoint in v-Src-expressing cells. v-Src induces cell cycle changes—such as the accumulation of the 4N cell population—and increases the number of binucleated cells, which is accompanied by an excess number of centrosomes. Time-lapse analysis of v-Src-expressing cells showed that cytokinesis failure is caused by cleavage furrow regression. Microscopic analysis revealed that v-Src induces delocalization of cytokinesis regulators including Aurora B and Mklp1. Tetraploid cell formation is one of the causes of chromosome instability; however, tetraploid cells can be eliminated at the tetraploidy checkpoint. Interestingly, v-Src weakens the tetraploidy checkpoint by inhibiting the nuclear exclusion of the transcription coactivator YAP, which is downstream of the Hippo pathway and its nuclear exclusion is critical in the tetraploidy checkpoint. We also discuss the relationship between v-Src-induced chromosome instability and growth suppression in v-Src-induced oncogenesis.

Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition

“…Although Src, to our knowledge, has not been directly implicated with maintaining mitotic fidelity, it has been shown to promote MT nucleation and regrowth (Colello et al, 2010) by binding to γ-tubulin complexes (Kukharskyy et al, 2004). In addition, Src was found to facilitate spindle orientation (Nakayama et al, 2012), and oncogenic v-Src has been associated with cytokinesis failure (Nakayama et al, 2017). This study revealed that Src inhibition results in increased MT polymerization rates, thus exacerbating the CIN phenotype imposed by Mad2 loss.…”

The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

“…v-Src regulates proliferation and cell survival through modification of growth regulatory signal transduction and affects migration by acting on actin cytoskeleton remodeling (2,5). In addition to these oncogenic effects, suppression of cell proliferation has been observed under some experimental conditions (2,(5)(6)(7). In one experiment (6), we used three cell lines, HeLa S3, HCT116, and NIH3T3, capable of inducing doxycycline (Dox) 2 concentration-dependent expression of v-Src.…”

“…Furthermore, v-Src induces chromosome bridge formation through the caffeine-sensitive DNA damage response (25). This can lead to further cytokinesis failure by attenuating the abscission checkpoint through Aurora B delocalization from the spindle midbody (7). Therefore, v-Src-induced disturbance of cell division can generate genetic diversity, and this pathway may be involved in the oncogenic effect of v-Src.…”

Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint

“…Although, to our knowledge, Src has not been directly implicated with maintaining mitotic fidelity, Src has been shown to promote microtubule nucleation and regrowth (Colello et al , 2010) by binding to gamma-tubulin complexes (Kukharskyy et al , 2004). Additionally, Src was found to facilitate spindle orientation (Nakayama et al , 2012), and oncogenic v-Src has been associated with cytokinesis failure (Nakayama et al , 2017). This study revealed that Src inhibition results in increased MT polymerization rates, thus exacerbating the CIN phenotype imposed by Mad2 loss.…”