title: Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis.
abstract: 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 the 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.
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sandra
authors.identifier: http://orcid.org/0000-0002-5099-8070
authors.initials: S
authors.lastname: Kümper
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Faraz K
authors.initials: FK
authors.lastname: Mardakheh
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Maggie
authors.initials: M
authors.lastname: Yeo
authors.affiliation: Experimental Pathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stamp
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Paul
authors.affiliation: Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0002-8242-4901
authors.initials: J
authors.lastname: Worboys
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Amine
authors.initials: A
authors.lastname: Sadok
authors.affiliation: Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Claus
authors.initials: C
authors.lastname: Jørgensen
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Guichard
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, London, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Marshall
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D049109:Cell Proliferation; D055786:Gene Knockout Techniques; D008545:Melanoma / Q000473:pathology; D051379:Mice; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054460:rho-Associated Kinases
keywords: ROCK; actin cytoskeleton; actomyosin contractility; cancer biology; cell biology; cell proliferation; cellular senescence; mouse; rho kinase