The tumor suppressor activity of SOCS-1.
SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 deficient mice die within the first three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 -/- fibroblasts are more sensitive than wild type fibroblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.
Rottapel
Robert
R
Department of Immunology, University of Toronto, Canada. rottapel@oci.utoronto.ca
Ilangumaran
Subburaj
S
Neale
Christopher
C
La Rose
Jose
J
Ho
Jenny M-Y
JM
Nguyen
Melody H-H
MH
Barber
Dwayne
D
Dubreuil
Patrice
P
de Sepulveda
Paulo
P
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D053614:Janus Kinase 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains; D000097764:ETS Translocation Variant 6 Protein
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D016374:Oncogene Proteins v-abl; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse