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Abstract
An increase in chromosome number, or polyploidization, is associated with a variety of biological changes including breeding of cereal crops and flowers, terminal differentiation of specialized cells such as megakaryocytes, cellular stress and oncogenic transformation. Yet it remains unclear how cells tolerate the major changes in gene expression, chromatin organization and chromosome segregation that invariably accompany polyploidization. We show here that cancer cells can initiate increases in chromosome number by inhibiting cell division through activation of glycoprotein1b alpha (GpIbα), a component of the c-Myc signaling pathway. We are able to recapitulate cytokinesis failure in primary cells by overexpression of GpIbα in a p53-deficient background. GpIbα was found to localize to the cleavage furrow by microscopy analysis and, when overexpressed, to interfere with assembly of the cellular cortical contraction apparatus and normal division. These results indicate that cytokinesis failure and tetraploidy in cancer cells are directly linked to cellular hyperproliferation via c-Myc induced overexpression of GpIbα.
Highlights
The transition from the restrained and controlled growth of normal cells to the accelerated and dysregulated growth of cancer cells requires multiple changes, including enhancement of the signaling pathways controlling division and survival
glycoprotein1b alpha (GpIba) overexpression caused failure of cytokinesis GpIba is widely overexpressed in a variety of tumors and tumor cell lines and GpIba overexpression gives rise to tetraploidy in primary human foreskin fibroblasts
Many other mitotic and cytokinesis defects including anaphase bridges, lagging chromosomes and micronuclei, demonstrated similar trends after GpIba knockdown in tested cancer cells (Figure 1B and C), showing that overexpression of GpIba is a significant cause of cytokinesis failure and mitotic defects in malignant cells
Summary
The transition from the restrained and controlled growth of normal cells to the accelerated and dysregulated growth of cancer cells requires multiple changes, including enhancement of the signaling pathways controlling division and survival. Since GI is strongly associated with senescence and apoptosis [6,7,8], it is unclear how cells tolerate the deleterious effects of GI long enough for these cellular evolutionary steps to occur. It is unclear whether the mechanisms that cause polyploidization are directly related to the signals that cause enhanced growth or whether they are an indirect consequence of elevated proliferation rates
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