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dc.contributor.authorMartín, Alberto-
dc.contributor.authorSalvador, Fernando-
dc.contributor.authorMoreno-Bueno, Gema-
dc.contributor.authorFloristán, Alfredo-
dc.contributor.authorCuevas, Eva P.-
dc.contributor.authorMorales, Saleta-
dc.contributor.authorSantos, Vanesa-
dc.contributor.authorCsiszar, Katalin-
dc.contributor.authorPortillo, Francisco-
dc.contributor.authorCano, Amparo-
dc.identifierdoi: 10.15252/embj.201489975-
dc.identifiere-issn: 1460-2075-
dc.identifierissn: 0261-4189-
dc.identifier.citationEMBO Journal 34(8): 1090-1109 (2015)-
dc.description.abstractLysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy.-
dc.description.sponsorshipThis work has been supported by grants from the Spanish Ministry of Economy and Innovation SAF2010-21143 (AC), SAF2010-20175 (GMB), SAF2013-44739-R (AC and FP) and CONSOLIDER-INGENIO 2010 CSD2007-00017 (AC); the AICR (12-1057) (AC and AM), the Spanish Instituto de Salud Carlos III [(RETIC-RD12/0036/0007 (AC), RETICC-RD12/0036/0054 (AB), PI13/00132 (GMB)], Comunidad de Madrid (S2010/BMD-2303) (AC and GMB) and AECC-2011 (GMB). AM and EPC are founded by postdoctoral contracts from S2010/BMD-2303 and AICR grants, respectively; FS was founded by a Jae-pre contract from the CSIC; and SM and VS are founded by technician contracts from the RETIC-RD12/0036/0007 and AICR grants, respectively.-
dc.publisherNature Publishing Group-
dc.subjectSquamous cell carcinoma-
dc.subjectEpidermal differentiation-
dc.subjectLoxl2 mouse models-
dc.subjectMale sterility-
dc.titleLysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression-
dc.description.versionPeer Reviewed-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderConsejo Superior de Investigaciones Científicas (España)-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderComunidad de Madrid-
dc.contributor.funderAsociación Española Contra el Cáncer-
dc.contributor.funderAmerican Institute for Cancer Research-
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