title: Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells.
abstract: Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.
authors.affiliation: Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049, Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Parrillas
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Muñoz
authors.forename: Borja L
authors.initials: BL
authors.lastname: Holgado
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Graciela
authors.initials: G
authors.lastname: Cascio
authors.forename: Pilar
authors.initials: P
authors.lastname: Lucas
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Rodríguez-Frade
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carrera
authors.forename: Karel Hm
authors.initials: KH
authors.lastname: van Wely
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
mesh_terms: D000818:Animals; D015703:Antigens, CD; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D064199:Cdc20 Proteins; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D056741:Cyclin D / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008677:Metaphase; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D064249:Securin; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D056741:Cyclin D; D019927:Cyclin E; C108944:SOCS1 protein, human; D064249:Securin; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex