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.