Figure 5.

Regulation of the ‘polyploidization–depolyploidization' cascade. Diploid cells (2n, 2C) can become tetraploid (4n, 4C) as a consequence of endoreplication, mitotic errors and cell-to-cell fusion (see also Figure 2), a phenomenon that is favored by some oncogenes (e.g., aurora kinase A, AURKA) and prevented by many cell cycle checkpoints including the SAC. Freshly generated tetraploids normally undergo apoptosis or are permanently blocked in the G₁ phase of the cell cycle, due to the activity of tumor suppressors including LATS2, TP53 and BAX. When such a tetraploidy control is deficient (for instance owing to the overexpression of the BAX antagonist BCL-2, when TP53 is inactivated by genetic or epigenetic events or in the presence of the viral oncoprotein E6), tetraploids illicitly proliferate and reach the G₂ phase of the cell cycle. Depolyploidization most often occurs via MD, which is prevented by centrosome coalescence (involving action-cortical forces and motor protein like KIFC1). Alternatively, TP53 mediates the apoptotic elimination of tetraploid cells that might have illicitly reached the G₂ phase of the cell cycle. Some oncogenes (e.g., MOS, NUMA1), dysfunctions of the SAC and/or of the TP53 system all favor the overcoming of centrosome coalescence, MD and hence depolyploidization, leading to the generation of aneuploid, most often pseudodiploid (2n± × , ∼2C), cells, which may contain 0–4 centrosomes. These aneuploid cells are normally unviable either because of the absence of centrosomes or to nullisomies and/or polysomies that are incompatible with life. Moreover, the proliferation of aneuploid cells is actively blocked by TP53, giving rise to the so-called ‘non-diploidy intolerance'. In rare instances (for instance when the TP53 system is inactive), pseudodiploids may bypass the apoptotic control and proliferate. Frequently, these cells display an increased tumorigenic potential and hence, activity support oncogenesis. Thicker arrows represent the most common events in the ‘polyploidization–depolyploidization' cascade. Additional details in text. C, DNA content of a haploid nucleus; KT, kinetochore; MT, microtubule; n=number of chromosomes in the haploid set (23 for humans)