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The interplay between centrosomes and the Hippo tumor suppressor pathway

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Abstract

Centrosome amplification is a common feature of both solid and hematological human malignancies. Extra centrosomes are not merely innocent bystanders in cancer cells, but rather promote tumor progression by disrupting normal cellular architecture and generating chromosome instability. Consequently, centrosome amplification correlates with advanced tumor grade and overall poor clinical prognosis. By contrast, extra centrosomes are adversely tolerated in non-transformed cells and hinder cell proliferation. This suggests that in addition to acquiring extra centrosomes, cancer cells must also adapt to overcome the deleterious consequences associated with them. Here, we review evidence that implicates core components of the Hippo tumor suppressor pathway as having key roles in both the direct and indirect regulation of centrosome number. Intriguingly, functional inactivation of the Hippo pathway, which is common across broad spectrum of human cancers, likely represents one key adaptation that enables cancer cells to tolerate extra centrosomes.

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Abbreviations

CIN:

Chromosome instability

CDKN1A:

Cyclin-dependent kinase inhibitor 1A

LATS1, LATS2:

Large tumor suppressor kinases 1 and 2

Mats:

Mps1 binder (MOB)

Mps1:

Monopolor spindle 1

MST1, MST2:

Mammalian sterile 20-like kinases 1 and 2

NDR1/2:

N-Myc downstream regulated 1 and 2 kinases

Nek2A:

NIMA-related kinase 2A

NF2:

Neurofibromin 2

SAS6:

Spindle assembly abnormal protein 6

TAZ:

Transcriptional co-activator with PDZ-binding motif

TEAD:

Transcriptional enhancer activation domain

YAP:

Transcriptional co-activator yes-associated protein

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Acknowledgments

A.F.B is supported by a Biomolecular Pharmacology Training Grant from the NIH/NIGMS (5T32GM008541). N.J.G is the Aram V. Chobanian Assistant Professor of Medicine in the Shamim and Ashraf Dahod Breast Cancer Research Laboratories and is supported in part by grants from the Richard and Susan Smith Family Foundation, the Searle Scholars Program, the Karin Grunebaum Cancer Research Foundation, and the NIH/NCI (K99/R00 CA154531-01).

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Correspondence to Neil J. Ganem.

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Bolgioni, A.F., Ganem, N.J. The interplay between centrosomes and the Hippo tumor suppressor pathway. Chromosome Res 24, 93–104 (2016). https://doi.org/10.1007/s10577-015-9502-8

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