title: SUMO-modified insulin-like growth factor 1 receptor (IGF-1R) increases cell cycle progression and cell proliferation.
abstract: Increasing number of studies have shown nuclear localization of the insulin-like growth factor 1 receptor (nIGF-1R) in tumor cells and its links to adverse clinical outcome in various cancers. Any obvious cell physiological roles of nIGF-1R have, however, still not been disclosed. Previously, we reported that IGF-1R translocates to cell nucleus and modulates gene expression by binding to enhancers, provided that the receptor is SUMOylated. In this study, we constructed stable transfectants of wild type IGF1R (WT) and triple-SUMO-site-mutated IGF1R (TSM) using igf1r knockout mouse fibroblasts (R-). Cell clones (R-WT and R-TSM) expressing equal amounts of IGF-1R were selected for experiments. Phosphorylation of IGF-1R, Akt, and Erk upon IGF-1 stimulation was equal in R-WT and R-TSM. WT was confirmed to enter nuclei. TSM did also undergo nuclear translocation, although to a lesser extent. This may be explained by that TSM heterodimerizes with insulin receptor, which is known to translocate to cell nuclei. R-WT proliferated substantially faster than R-TSM, which did not differ significantly from the empty vector control. Upon IGF-1 stimulation G1-S-phase progression of R-WT increased from 12 to 38%, compared to 13 to 20% of R-TSM. The G1-S progression of R-WT correlated with increased expression of cyclin D1, A, and CDK2, as well as downregulation of p27. This suggests that SUMO-IGF-1R affects upstream mechanisms that control and coordinate expression of cell cycle regulators. Further studies to identify such SUMO-IGF-1R dependent mechanisms seem important.
authors.affiliation: Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.|Laboratory of Aquatic Animal Nutrition Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Waraky
authors.affiliation: Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Felix
authors.initials: F
authors.lastname: Haglund
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.|Department of Laboratory Medicine (LABMED) H5, Division of Clinical Immunology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Prasoon
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.affiliation: Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dudi
authors.initials: D
authors.lastname: Warsito
authors.affiliation: Department of Oncology and Pathology, CCK R8: 04, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D016193:G1 Phase; D005838:Genotype; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D015398:Signal Transduction; D058207:Sumoylation; D013997:Time Factors; D014162:Transfection
chemical_list: C530105:Ccnd1 protein, mouse; D019925:Cyclin A; D017451:Receptors, Somatomedin; D019938:Cyclin D1; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: IGF-1R; SUMOylation; cancer; cell cycle; proliferation