STATs in oncogenesis

Bowman, Tammy; Garcia, Roy; Turkson, James; Jove, Richard

doi:10.1038/sj.onc.1203527

Cited by 1,623 publications

(1,501 citation statements)

References 167 publications

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“…STAT3 is constitutively phosphorylated and activated in various primary human tumors and transformed cell lines, and has been implicated in tumorigenesis [2,3,4]. However, the molecular mechanisms of the persistent activation of STAT3 in human tumor cells remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The transcriptional factor plays crucial roles in early embryonic development as well as in other biological responses, including cell growth and apoptosis [1,2,3]. Of importance, STAT3 is constitutively activated in oncogene-transformed cells and various primary tumors and cell lines [4]. Several tumor viruses are also associated with STAT3 activation.…”

Section: Introductionmentioning

confidence: 99%

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Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Muromoto

Ikeda

Okabe

et al. 2009

Biochemical and Biophysical Research Communications

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The Epstein-Barr virus (EBV)-encoded latency protein EBNA2 is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. Here, we show that EBNA2 interacts with STAT3, a signal transducer for an interleukin-6 family cytokine, and enhances the transcriptional activity of STAT3 by influencing its DNA-binding activity. Furthermore, EBNA2 cooperatively acts on STAT3 activation with LMP1. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3.3

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Muromoto

Ikeda

Okabe

et al. 2009

Biochemical and Biophysical Research Communications

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“…OA Timofeeva et al suppress oncogenesis and metastatic growth (Bowman et al, 2000;Danial and Rothman, 2000;Huang et al, 2002), and STAT1 deficiency has been found in some tumors (Abril et al, 1998;Sun et al, 1998;Pansky et al, 2000). Although Stat1-deficient mice do not display a heightened incidence of spontaneous neoplasms, they are more sensitive to chemical induction of tumors (Kaplan et al, 1998;Levy and Gilliland, 2000).…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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“…Upon activation by tyrosine phosphorylation, STATs enter the nucleus and modulate expression of genes involved in many functions, including survival, differentiation and apoptosis (Horvath, 2000). Aberrant activation of STATs, especially STAT5, is found in numerous cancers, including hematopoietic cancers (Frank, 1999;Bowman et al, 2000;Lin et al, 2000). Chronic myelogenous leukemia (CML) is a prototypical tumor displaying constitutive STAT5 activation.…”

Section: Introductionmentioning

confidence: 99%

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

2006

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Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high interspecies homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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STATs in oncogenesis

Cited by 1,623 publications

References 167 publications

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

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