TY - JOUR
T1 - Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha
AU - Brender, C
AU - Lovato, P
AU - Sommer, V H
AU - Woetmann, A
AU - Mathiesen, A-M
AU - Geisler, C
AU - Wasik, M
AU - Ødum, N
N1 - Keywords: Amino Acid Substitution; Cell Division; Cell Line, Tumor; Humans; Interferon-alpha; Lymphoma, T-Cell; Mutagenesis, Site-Directed; Repressor Proteins; Suppressor of Cytokine Signaling Proteins; Transcription Factors; Transcription, Genetic
PY - 2005
Y1 - 2005
N2 - Signal transducer and activator of transcription (Stat)3 is constitutively activated in cutaneous T-cell lymphoma (CTCL), where it protects tumour cells against apoptosis. The constitutive activation of Stat3 leads to a constitutive expression of suppressor of cytokine signalling (SOCS)-3. In healthy cells, SOCS-3 is transiently expressed following cytokine stimulation and functions as a negative feedback inhibitor of the Stat3-activating kinases. Here, we attempt to resolve the apparent paradox of a simultaneous SOCS-3 expression and Stat3 activation in the same cells. We show that (i) SOCS-3 expression in tumour cells is equal to or higher than in cytokine-stimulated nonmalignant T cells, (ii) SOCS-3 is not mutated in CTCL, (iii) overexpression of SOCS-3 blocks IFNalpha-mediated growth inhibition without affecting Stat3 activation, growth, and apoptosis, and (iv) inhibition of SOCS-3 by a dominant negative Stat3 (Stat3D) increases the IFNalpha-mediated growth inhibition. Taken together, these data show that SOCS-3 does not inhibit Stat3 activation, growth, and survival in CTCL. In contrast, SOCS3 protects tumour cells against growth inhibition by IFNalpha. Unlike SOCS-1, SOCS-3 is therefore not a tumour suppressor but rather a protector of tumour cells.
AB - Signal transducer and activator of transcription (Stat)3 is constitutively activated in cutaneous T-cell lymphoma (CTCL), where it protects tumour cells against apoptosis. The constitutive activation of Stat3 leads to a constitutive expression of suppressor of cytokine signalling (SOCS)-3. In healthy cells, SOCS-3 is transiently expressed following cytokine stimulation and functions as a negative feedback inhibitor of the Stat3-activating kinases. Here, we attempt to resolve the apparent paradox of a simultaneous SOCS-3 expression and Stat3 activation in the same cells. We show that (i) SOCS-3 expression in tumour cells is equal to or higher than in cytokine-stimulated nonmalignant T cells, (ii) SOCS-3 is not mutated in CTCL, (iii) overexpression of SOCS-3 blocks IFNalpha-mediated growth inhibition without affecting Stat3 activation, growth, and apoptosis, and (iv) inhibition of SOCS-3 by a dominant negative Stat3 (Stat3D) increases the IFNalpha-mediated growth inhibition. Taken together, these data show that SOCS-3 does not inhibit Stat3 activation, growth, and survival in CTCL. In contrast, SOCS3 protects tumour cells against growth inhibition by IFNalpha. Unlike SOCS-1, SOCS-3 is therefore not a tumour suppressor but rather a protector of tumour cells.
U2 - 10.1038/sj.leu.2403610
DO - 10.1038/sj.leu.2403610
M3 - Journal article
C2 - 15618960
SN - 0887-6924
VL - 19
SP - 209
EP - 213
JO - Leukemia
JF - Leukemia
IS - 2
ER -