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.

Keywords: YAP; chromosome instability; cytokinesis; tetraploidy checkpoint; v-Src.

Figure 1

v-Src induces cytokinesis failure. The chromosomal passenger complex (CPC) and centralspindlin complex are localized at the spindle midzone; however, v-Src causes delocalization of the components of these complexes. As a result, cytokinesis fails due to regression of the cleavage furrow, resulting in the formation of binucleated cell.

Figure 2

v-Src weakens the tetraploidy checkpoint. LATS kinases, which are activated in tetraploid cells, phosphorylate YAP, leading to exclusion of YAP from the nucleus. In addition, LATS activation results in stabilization of p53 through inhibition of MDM2. As a result, tetraploid cells are removed at this tetraploidy checkpoint. v-Src inhibits YAP phosphorylation by inhibiting LATS, possibly through activation of the PI3K pathway.

Figure 3

Genetic diversification in v-Src-expressing cells. v-Src induces tetraploidization through cytokinesis failure. The activation of the tetraploidy checkpoint in tetraploid cells is suppressed by v-Src. Tetraploid cells give rise to chromosome mis-segregation, leading to genetic diversification. v-Src causes growth suppression; however, among cells with broad genetic diversity, cells resistant to v-Src-induced growth suppression can evolve and continue to proliferate.