Enforced SOCS1 and SOCS3 expression attenuates Lck-mediated cellular transformation.
Lck is an Src family protein tyrosine kinase with predominant T cell expression. Aberrant expression or activation of Lck kinase has been reported in both lymphoid and non-lymphoid malignancies. We showed previously that the signal transduction pathway involving Janus kinase (JAK) and signal transducer and activator of transcription (STAT) is constitutively activated and contributes to Lck-mediated oncogenesis. Under normal physiological conditions, active STAT proteins induce the expression of suppressor of cytokine signaling (SOCS) family proteins to inhibit further JAK/STAT signaling. It is not fully understood whether and how SOCS-mediated negative feedback control is dysregulated in Lck-transformed cells. Here we report that two SOCS family members, SOCS1 and SOCS3, are not expressed in Lck-transformed LSTRA leukemia. While SOCS1 gene is silenced by DNA hypermethylation, loss of SOCS3 expression is through a mechanism independent of epigenetic silencing by DNA methylation. Furthermore, ectopic expression of SOCS1 or SOCS3 leads to reduced cell proliferation and increased apoptosis in Lck-transformed cells. This is consistent with the attenuation of Lck kinase activity by exogenous SOCS1 or SOCS3 expression. Downstream STAT5 activity is also inhibited as shown by reduced STAT5 tyrosine phosphorylation and in vitro DNA binding. All together, our data highlight the importance of silencing multiple SOCS genes in tumorigenesis and support the roles of SOCS1 and SOCS3 as tumor suppressors toward oncogenic Lck kinase.
Cooper
John C
JC
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37221, USA.
Shi
Mingjian
M
Chueh
Fu-Yu
FY
Venkitachalam
Srividya
S
Yu
Chao-Lan
CL
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*
C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)