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dc.contributor.authorPickering, K. A.
dc.contributor.authorGilroy, K.
dc.contributor.authorCassidy, J. W.
dc.contributor.authorFey, S. K.
dc.contributor.authorNajumudeen, A. K.
dc.contributor.authorZeiger, L. B.
dc.contributor.authorVincent, D. F.
dc.contributor.authorGay, D. M.
dc.contributor.authorJohansson, J.
dc.contributor.authorFordham, R. P.
dc.contributor.authorMiller, B.
dc.contributor.authorClark, W.
dc.contributor.authorHedley, A.
dc.contributor.authorUnal, E. B.
dc.contributor.authorKiel, C.
dc.contributor.authorMcGhee, E.
dc.contributor.authorMachesky, L. M.
dc.contributor.authorNixon, C.
dc.contributor.authorJohnsson, A. E.
dc.contributor.authorBain, M.
dc.contributor.authorStrathdee, D.
dc.contributor.authorvan Hoof, S. R.
dc.contributor.authorMedema, J. P.
dc.contributor.authorAnderson, K. I.
dc.contributor.authorBrachmann, S. M.
dc.contributor.authorStucke, V. M.
dc.contributor.authorMalliri, A.
dc.contributor.authorDrysdale, M.
dc.contributor.authorTurner, M.
dc.contributor.authorSerrano, L.
dc.contributor.authorMyant, K.
dc.contributor.authorCampbell, A. D.
dc.contributor.authorSansom, O. J.
dc.date.accessioned2021-01-04T16:19:36Z
dc.date.available2021-01-04T16:19:36Z
dc.date.issued2021-01-04
dc.date.submitted2017-06-19
dc.identifier.others41467-020-20255-4
dc.identifier.other20255
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/315657
dc.description.abstractAbstract: RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2−/−Vav3−/−Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
dc.languageen
dc.publisherNature Publishing Group UK
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectArticle
dc.subject/631/67/70
dc.subject/631/67/1504/1885/1393
dc.subject/38/91
dc.subject/13/51
dc.subject/13/106
dc.subject/14/33
dc.subject/64/60
dc.subjectarticle
dc.titleA RAC-GEF network critical for early intestinal tumourigenesis
dc.typeArticle
dc.date.updated2021-01-04T16:19:36Z
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume12
dc.identifier.doi10.17863/CAM.62771
dcterms.dateAccepted2020-11-17
rioxxterms.versionofrecord10.1038/s41467-020-20255-4
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidNajumudeen, A. K. [0000-0002-3764-5721]
dc.contributor.orcidZeiger, L. B. [0000-0002-8712-3112]
dc.contributor.orcidGay, D. M. [0000-0002-7407-1245]
dc.contributor.orcidMachesky, L. M. [0000-0002-7592-9856]
dc.contributor.orcidNixon, C. [0000-0002-8085-2160]
dc.contributor.orcidJohnsson, A. E. [0000-0002-0018-700X]
dc.contributor.orcidStrathdee, D. [0000-0003-2959-4327]
dc.contributor.orcidAnderson, K. I. [0000-0002-9324-9598]
dc.contributor.orcidMalliri, A. [0000-0001-6848-090X]
dc.contributor.orcidTurner, M. [0000-0002-3801-9896]
dc.contributor.orcidSerrano, L. [0000-0002-5276-1392]
dc.contributor.orcidMyant, K. [0000-0001-8017-1093]
dc.contributor.orcidCampbell, A. D. [0000-0003-3930-1276]
dc.contributor.orcidSansom, O. J. [0000-0001-9540-3010]
dc.identifier.eissn2041-1723


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)