Stat3 as an Oncogene

Abstract

STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription. The Stat3-C molecule in immortalized fibroblasts causes cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the activated Stat3 molecule by itself can mediate cellular transformation and the experiments focus attention on the importance of constitutive Stat3 activation in human tumors.

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

“…These proteins are known to promote tumor growth. Indeed, an experimentally engineered STAT3-dimer can readily transform cells by preventing apoptosis (Bromberg et al, 1999). Consistent with these results, the expression of its inhibitor, SOCS3, has been shown to be downregulated in some hepatomas (Yoshikawa et al, 2001).…”

“…In contrast to its feedback regulation in normal cells, STAT3 is constitutively activated in a number of human cancers by autocrine growth factors or activated oncogenes (Buettner et al, 2002) which, in turn, activates the expression a number of cellular protooncogenes such as c-myc, c-fos, M-ras, and c-Met (Yang et al, 2005); cell cycle regulating proteins such as cyclins D1 and B1, and Cdc2 (Bromberg et al, 1999); and antiapoptotic proteins such as Bcl2, mcl-1 and Bcl-X L (Buettner et al, 2002). These proteins are known to promote tumor growth.…”

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

“…Forced expression of STAT3C (a construct constitutively activated by spontaneous dimmer formation) in immortalized fibroblasts induced cell transformation and tumor formation in nude mice (Bromberg et al, 1999). Blocking STAT3 activity with chemical reagents and dominant-negative forms inhibited the tumor cell growth in nude mice (Blaskovich et al, 2003;Wei et al, 2003).…”

“…STAT3 regulates cell cycle-associated cyclin D1 and antiapoptotic Bcl-2 and Bcl-xl, contributing to the proliferation of cancer cells (Masuda et al, 2002;O'Shea et al, 2002). STAT3C, a construct constitutively activated by spontaneous dimmer formation, acquired the transforming activity scored by colony growth in soft agar and its tumor-forming potential in nude mice (Bromberg et al, 1999). Conversely, dominant-negative forms of STAT3 suppressed cell transformation with v-src oncogene (Bromberg et al, 1998) and the epidermal growth factor receptor (EGFR)-mediated autocrine growth of transformed epithelial cells (Grandis et al, 1998).…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…In addition, STAT3 levels are elevated in a number of human cancers, including breast cancer, prostate cancer, head and neck cancers, and hematologic malignancies (Bowman et al, 2000). Furthermore, STAT3 induces cellular transformation in vitro and tumor formation in nude mice (Bromberg et al, 1999). When acetylated, STAT3 promotes p100 processing to p52 and thereby activates NF-kB (Nadiminty et al, 2006, Figure 2).…”