Fig. 6

Proposed model for the role of mutp53 and Nek2 in promoting tumorigenesis. In tumors heterozygous for mutp53 there is a mixed population of heterozygous cells (H/+) and cells that underwent spontaneous LOH (H/−). Genotoxic stress, such as γ-irradiation, leads to slow proliferation and expansion of H/+ population due to the presence of wtp53 that can induce cell cycle checkpoint and arrest. On the other hand, H/− cells continue unrestricted proliferation, taking over the H/+ population. In both cases, absence of wtp53 in H/− leads to increased cell proliferation and to centrosome amplification. To avoid multipolar mitosis and cell death of H/− cells with centrosome amplification, mutp53 utilizes Nek2 to induce centrosome clustering to promote bipolar mitosis and cell survival. Centrosome clustering process lengthens mitosis which then leads to increased chromosomal instability and thus enhancing tumor progression and metastasis. Our model proposes Nek2 as an Achilles heel, for tumor cells with mutp53, that can be used as a therapeutic target to prevent p53 LOH and cells that have lost the wtp53 alleles