Stat3 as an oncogene

STATs are latent transcription factors that mediate cytokine- and growth fa ctor-directed transcription. In many human cancers and transformed cell lin es, Stat3 is persistently activated, and in cell culture, active Stat3 is e ither required for transformation, enhances transformation, or blocks apopt osis. We report that substitution of two cysteine residues within the C-ter minal loop of the SH2 domain of Stat3 produces a molecule that dimerizes sp ontaneously, binds to DNA, and activates transcription. The Stat3-C molecul e in immortalized fibroblasts causes cellular transformation scored by colo ny formation in soft agar and tumor formation in nude mice. Thus, the activ ated Stat3 molecule by itself can mediate cellular transformation and the e xperiments focus attention on the importance of constitutive Stat3 activati on in human tumors.