title: Galectin-1 interacts with the {alpha}5{beta}1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27.
abstract: Surface binding of galectin family members has the potential to link distinct glycan structures to growth regulation. Therefore, we addressed the antiproliferative potential of galectin-1 (Gal-1) in a panel of carcinoma cell lines. We discovered growth inhibition by Gal-1 in epithelial tumor cell lines from different origins and provide evidence that this effect requires functional interaction with the alpha5beta1 integrin. Antiproliferative effects result from inhibition of the Ras-MEK-ERK pathway and consecutive transcriptional induction of p27. We have further identified two Sp1-binding sites in the p27 promoter as crucial for Gal-1 responsiveness. Inhibition of the Ras-MEK-ERK cascade by Gal-1 increased Sp1 transactivation and DNA binding due to reduced threonine phosphorylation of Sp1. Furthermore, Gal-1 induced p21 transcription and selectively increased p27 protein stability. Gal-1-mediated accumulation of p27 and p21 inhibited cyclin-dependent kinase 2 activity and ultimately resulted in G(1) cell cycle arrest and growth inhibition. These data define a novel mechanism whereby Gal-1 regulates epithelial tumor cell homeostasis via carbohydrate-dependent interaction with the alpha5beta1 integrin.
authors.affiliation: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Fischer
authors.forename: Hugo
authors.initials: H
authors.lastname: Sanchez-Ruderisch
authors.forename: Martina
authors.initials: M
authors.lastname: Welzel
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.forename: Levon
authors.initials: L
authors.lastname: Khachigian
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Detjen
authors.forename: Stefan
authors.initials: S
authors.lastname: Rosewicz
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D037483:Galectin 1 / Q000378:metabolism*; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics; D013912:Threonine; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D037483:Galectin 1; D039081:Integrin alpha5beta1; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D013912:Threonine; D051357:Cyclin-Dependent Kinase 2; D020930:MAP Kinase Kinase Kinases