Galectin-1 interacts with the {alpha}5{beta}1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27.
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.
Fischer
Christian
C
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany.
Sanchez-Ruderisch
Hugo
H
Welzel
Martina
M
Wiedenmann
Bertram
B
Sakai
Toshiyuki
T
André
Sabine
S
Gabius
Hans-Joachim
HJ
Khachigian
Levon
L
Detjen
Katharina M
KM
Rosewicz
Stefan
S
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
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