Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Carrier Proteins / physiology*
-
Cell Division
-
Cell Transformation, Neoplastic / metabolism
-
DNA-Binding Proteins / metabolism
-
Fibroblasts / metabolism
-
Fusion Proteins, bcr-abl / metabolism
-
Genes, Tumor Suppressor / physiology*
-
Hematopoietic Stem Cells / physiology*
-
Janus Kinase 2
-
Mice
-
Mice, Inbred BALB C
-
Mice, Nude
-
Mitogen-Activated Protein Kinases / metabolism
-
Oncogene Proteins v-abl / genetics
-
Oncogene Proteins v-abl / metabolism
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / metabolism
-
Phosphorylation
-
Protein-Tyrosine Kinases / physiology
-
Proto-Oncogene Proteins c-kit / genetics
-
Proto-Oncogene Proteins c-kit / metabolism
-
Proto-Oncogene Proteins*
-
Repressor Proteins / physiology
-
Retroviridae / genetics
-
STAT1 Transcription Factor
-
Suppressor of Cytokine Signaling 1 Protein
-
Suppressor of Cytokine Signaling Proteins
-
Trans-Activators / metabolism
-
Transfection
-
p38 Mitogen-Activated Protein Kinases
-
src Homology Domains
Substances
-
Carrier Proteins
-
DNA-Binding Proteins
-
Oncogene Proteins v-abl
-
Oncogene Proteins, Fusion
-
Proto-Oncogene Proteins
-
Repressor Proteins
-
STAT1 Transcription Factor
-
Socs1 protein, mouse
-
Stat1 protein, mouse
-
Suppressor of Cytokine Signaling 1 Protein
-
Suppressor of Cytokine Signaling Proteins
-
TEL-JAK2 fusion protein, human
-
TEL-JAK2 fusion protein, mouse
-
Trans-Activators
-
Protein-Tyrosine Kinases
-
Proto-Oncogene Proteins c-kit
-
Fusion Proteins, bcr-abl
-
JAK2 protein, human
-
Jak2 protein, mouse
-
Janus Kinase 2
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases