000169227 001__ 169227 000169227 005__ 20260223164759.0 000169227 0247_ $$2doi$$a10.1002/path.5277 000169227 0248_ $$2sideral$$a148296 000169227 037__ $$aART-2019-148296 000169227 041__ $$aeng 000169227 100__ $$aCemeli, Tània 000169227 245__ $$aCytoplasmic cyclin D1 regulates glioblastoma dissemination 000169227 260__ $$c2019 000169227 5203_ $$aGlioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4–retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1‐Cdk4 overactivation. High levels of Ccnd1‐Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1‐Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1‐independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1‐Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane‐targeted Ccnd1. We conclude that Ccnd1‐Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1‐independent mechanisms. Therefore, inhibition of Ccnd1‐Cdk4 activity may be useful to hinder the dissemination of recurrent GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 000169227 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BFU2013-42895-P$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78826-P 000169227 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/ 000169227 590__ $$a5.979$$b2019 000169227 591__ $$aPATHOLOGY$$b6 / 78 = 0.077$$c2019$$dQ1$$eT1 000169227 591__ $$aONCOLOGY$$b41 / 244 = 0.168$$c2019$$dQ1$$eT1 000169227 592__ $$a2.724$$b2019 000169227 593__ $$aPathology and Forensic Medicine$$c2019$$dQ1 000169227 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000169227 700__ $$aGuasch-Vallés, Marta 000169227 700__ $$aNàger, Mireia 000169227 700__ $$aFelip, Isidre 000169227 700__ $$aCambray, Serafí 000169227 700__ $$aSantacana, Maria 000169227 700__ $$aGatius, Sònia 000169227 700__ $$aPedraza, Neus 000169227 700__ $$aDolcet, Xavier 000169227 700__ $$aFerrezuelo, Francisco 000169227 700__ $$0(orcid)0000-0002-0136-1049$$aSchuhmacher, Alberto J$$uUniversidad de Zaragoza 000169227 700__ $$aHerreros, Judit 000169227 700__ $$aGarí, Eloi 000169227 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000169227 773__ $$g248, 4 (2019), 501-513$$pJ. pathol.$$tJOURNAL OF PATHOLOGY$$x0022-3417 000169227 8564_ $$s13991441$$uhttps://zaguan.unizar.es/record/169227/files/texto_completo.pdf$$yVersión publicada 000169227 8564_ $$s2806220$$uhttps://zaguan.unizar.es/record/169227/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000169227 909CO $$ooai:zaguan.unizar.es:169227$$particulos$$pdriver 000169227 951__ $$a2026-02-23-14:54:54 000169227 980__ $$aARTICLE