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Page 6 of 20 Jusino et al. J Cancer Metastasis Treat 2018;4:43 I http://dx.doi.org/10.20517/2394-4722.2018.24

leading to abnormal mitosis and abnormal chromosome constitutions may contribute to malignant tumors .
[80]
Since then, our laboratory and those of others have worked towards the elucidation of the mechanisms and
consequences of centrosome aberrations in tumor initiation and progression. The centrosome is a small
organelle composed of a pair of centrioles surrounded by pericentriolar material (PCM) that serves as the
principal microtubule organizing center of vertebrate cells . The centrosome duplicates only once to ensure
[81]
proper spindle formation and equal chromosomal segregation during mitosis [82,83] . In order to maintain
chromosome stability, the centrosome duplication cycle and the cell cycle must be tightly coordinated [84-88] .
Laser ablation and microsurgical removal demonstrated that some immortalized mammalian cells (hTERT-
RPE and -HMECs) can cycle without centrioles/centrosomes; however, some epithelial cells like BSC-1 African
green monkey kidney cells go through G1 much more slowly or not at all if centrosomes are removed [89,90] .
Centrosome removal sensitizes cells to various external stimuli such as blue light, which results in p53-
dependent G1 arrest . Similarly, silencing of 14 (out of 15) centrosome components arrests cells in G1 by
[89]
activating p53, p21, p38, and inactivation of cyclin A-Cdk2 activity .
[91]
Failure in the control of the centrosome cycle or of cytokinesis leads to numerical and structural centrosome
aberrations, which have been identified in most cancer types [92-94] . A common centrosome aberration in
many cancers is centrosome amplification , which culminates in different degrees of aneuploidy (including
[94]
single chromosome gains/losses all the way to whole genome doubings) and chromosome instability,
thus contributing to intra-tumor heterogeneity. In order to maintain genomic stability, the cell cycle
machinery also regulates the centrosome cycle [84,88,95-99] . One model states that the centrosome duplication
cycle starts in G1-S when the pair of centrioles dissociates [88,100,101] . In a model proposed by Fukasawa ,
[88]
centrosome disengagement in late G1 is licensed by the phosphorylation of nucleophosmin (NPM) by
cyclin E/Cdk2 complexes [97,102-107] . Another model, evidenced by data from the Stearn group suggests that
centriole disengagement occurs during anaphase, that it involves separase, and that this event licenses
centriole duplication in the next cell cycle; in this model Cdk2 is required for centriole duplication, but not
for licensing . Our studies added additional complexity to these models, since the centrosomes from cdk4
-/-
[108]
-/-
mouse embryonic fibroblast did not achieve centrosome separation at G1/S, while these with a cdk2 genotype
achieved premature separation, and the premature separation defect was exacerbated in cdk2 cdk4 mouse
-/-
-/-
embryonic fibroblasts . Early studies from the Nigg’s group demonstrated that centriole duplication
[104]
requires the activation of E2F transcription factors and the activity of the Cdk2-cyclin A complex , and
[107]
the Leone laboratory demonstrated that repression by E2F3 played a major role in preventing premature
centriole duplication, centrosome amplification, and chromosome instability by controlling cyclin E levels
and cyclin E-dependent kinase activity . Although it is not entirely clear how the E2F activators (E2F1,
[109]
E2F2 and E2F3a) control centrosome duplication, our laboratory has shown that the E2F activators control
the transcription, protein stability, and protein levels of many targets that regulate the centrosome cycle and
mitosis, including cyclin E, Rb, Plk4, Nek2, Mps1, SgoL1, and cyclin B [35,109,110] .
Albeit elucidating the entire centrosome duplication cycle is still a work in progress, much is now known
about the cellular events controlling it, recently reviewed by Nigg and Holland . Centriole assembly is
[111]
controlled by phosphorylation of Ana2/STIL by Plk4; this event recruits Ana2 and Sas6 to initiate procentriole
formation [112,113] . Centriole biogenesis is controlled by interactions between Cdk2 and the SKP1-Cullin-F-
box E3 ligase βTrCP, where Cdk2 protects STIL from degradation by βTrCP ; STIL then interacts with
[114]
CPAP to complete centriole duplication . Cdk2 also controls the degradation of Mps1 in centrosomes to
[115]
control centriole duplication . Aurora kinase A (AURKA) is essential to the formation of a bipolar mitotic
[116]
spindle by regulating centrosome separation . The AURKA phosphorylation of Cdk1-cyclin B at G2
[117]
recruits the former to centrosomes, where it is activated to initiate mitotic entry . Centrosome localization
[118]
of Cdk1 and inhibition of Chk1 is present in mitosis to prevent premature activation of the Cdk1-cyclin
B complex . Accordingly, PLK1 regulates centrosome maturation , centrosome disjunction through
[119]
[120]
NEK2 , and centrosome microtubule-attachments . Also, NEK2 regulates centrosome separation by
[122]
[121]