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The tumor suppressor activity of SOCS-1
Robert Rottapel1, Subburaj Ilangumaran, Christopher Neale
1Department of Immunology, University of Toronto, Canada. rottapel@oci.utoronto.ca
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.
Insights
Suppressor of Cytokine Signaling-1 (SOCS-1) inhibits hematopoietic oncogene-driven proliferation and transformation. Loss of SOCS-1 function may collaborate with oncogenes, promoting tumor progression in myeloproliferative disorders.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Suppressor of Cytokine Signaling-1 (SOCS-1) is a key inhibitor of Janus kinase (Jak) signaling.
- SOCS-1 deficiency in mice leads to fatal myeloproliferative disorders due to excessive interferon signaling.
Purpose of the Study:
- To investigate the role of SOCS-1 in inhibiting proliferation signals mediated by various oncogenes in the hematopoietic system.
- To explore the mechanisms underlying SOCS-1's tumor suppressive functions.
Main Methods:
- Ectopic expression of SOCS-1 in hematopoietic cells.
- Utilizing mutant SOCS-1 forms to assess SH2 domain-dependent inhibition.
- Analyzing oncogene-induced transformation in SOCS-1 deficient fibroblasts.
- Assessing steady-state levels of oncogenic proteins in the presence of SOCS-1.
Main Results:
- SOCS-1 expression abolished proliferation induced by KIT, TEL-JAK2, and v-ABL, and reduced metastasis of BCR-ABL transformed cells.
- SOCS-1 did not inhibit v-SRC or RASV12 mediated transformation.
- A non-SH2 binding SOCS-1 mutant retained KIT inhibition but not TEL-JAK2 inhibition.
- SOCS-1 diminished TEL-JAK2 and v-ABL protein levels.
- SOCS-1 deficient fibroblasts exhibited increased sensitivity to spontaneous and oncogene-induced transformation.
Conclusions:
- SOCS-1 acts as a tumor suppressor by inhibiting proliferation signals from specific hematopoietic oncogenes.
- SOCS-1 employs multiple mechanisms, including SH2-dependent and independent pathways, for tumor suppression.
- Loss of SOCS-1 function may cooperate with hematopoietic oncogenes to drive tumor progression.