title: LRP5 negatively regulates differentiation of monocytes through abrogation of Wnt signalling.
abstract: Molecular changes involved in cell differentiation are only partially known. Circulating inflammatory cells need to differentiate to perform specialized functions in target tissues. Here, we hypothesized that low-density lipoprotein receptor-related protein 5 (LRP5) is involved, through its participation in the canonical Wnt/β-catenin signalling, in the differentiation process of monocytic cells. To this aim, we characterized differentiation mechanisms of HL60 cells and primary human monocytes. We show that silencing the LRP5 gene increased differentiation of HL60 cells and human monocytes, suggesting that LRP5 signalling abrogates differentiation. We demonstrate that the mechanisms behind this blockade include sequestration of β-catenin at the cellular membrane, inhibition of the Wnt signalling and increase of apoptosis. We further demonstrate the involvement of LRP5 and the Wnt/β-catenin signalling in the process because cellular differentiation can be rescued by the addition of downstream Wnt target genes to the monocytic cells.
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Borrell-Pagès
authors.forename: July Carolina
authors.initials: JC
authors.lastname: Romero
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism*; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D018922:HL-60 Cells; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C489427:MYC protein, human; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin
keywords: HL60; LRP5; apoptosis; cellular differentiation; macrophages