Elife. 2016 Jan 14;5. pii: e12203. doi: 10.7554/eLife.12203. [Epub ahead of print]
Kümper, S; Mardakheh, FK; McCarthy, A; Yeo, M; Stamp, GW; Paul, A; Worboys, J; Sadok, A; Jørgensen, C; Guichard, S; Marshall, CJ
Division of Cancer Biology, Institute of Cancer Research: Experimental Pathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom. Cancer Research UK Manchester Institute, Manchester, United Kingdom.
Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 350 scientific publications are based on research using Ozgene mice.