Identification of a Genetic Signature of Activated Signal Transducer and Activator of Transcription 3 in Human Tumors

Alvarez, James V.; Febbo, Phillip G.; Ramaswamy, Sridhar; Loda, Massimo; Richardson, Andrea L.; Frank, David A.

doi:10.1158/0008-5472.can-04-4281

Cited by 177 publications

(182 citation statements)

References 35 publications

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“…This suggested that STAT1 may also be regulating BCL6. Additionally, it has been shown that expression of activated STAT3 in fibroblasts leads to upregulation of BCL6 expression (Alvarez et al, 2005), raising the possibility that STAT3 may also regulate BCL6 expression. In addition to activating STAT5, IL-2 also can activate STAT1 and STAT3 (Frank et al, 1995).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

2006

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“…At the present time, the STAT3 transcriptional response is only partially understood, with a large number of STAT3 transcriptional targets being identified just in the last few months. 52,53 Further study of these STAT3 targets in the context of differentiating myeloid progenitors might be required before the full implication of STAT3 phosphorylation in MMM progenitors is completely appreciated.…”

Section: Discussionmentioning

confidence: 99%

Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia

et al. 2006

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An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunoblotting revealed phosphorylation of signal transducer and activator of transcription-3 (STAT3) in all four JAK2 with high V617F mutant allele burden and seven of eight with intermediate mutant allele burden, but only one of eight with wild-type JAK2 (Po0.001). In contrast, STAT5 phosphorylation was undetectable in patient MMM neutrophils; and phosphorylation of Akt and extracellular signal-regulated kinases (ERKs) failed to correlate with JAK2 mutation status. Apoptosis was lower in MMM neutrophils (median 41% apoptotic cells, n ¼ 50) compared to controls (median 66%, n ¼ 9) or other myeloproliferative disorder patients (median 53%, n ¼ 11; P ¼ 0.002). Apoptotic resistance in MMM correlated with anemia (P ¼ 0.01) and the JAK2-V617F (P ¼ 0.01). Indeed, apoptotic resistance was greatest in MMM neutrophils with high mutant allele burden (median 22% apoptosis, n ¼ 5) than with intermediate burden (median 39%, n ¼ 23) or wild-type JAK2 (median 47%, n ¼ 22; P ¼ 0.008). These results suggest that mutant JAK2 contributes to MMM pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis.

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“…STAT signaling is critical for normal cellular processes such as embryonic development, organogenesis and organ function, innate and adaptive immune function, regulation of cell differentiation, growth, and apoptosis [122][123][124][125][126][127]. In normal cells, STAT3 protein activation is strictly controlled to prevent unscheduled gene regulation, while constitutive activation of STAT3 has been detected in a wide number of human cancer cell lines and primary tumors, such as 50% of HCC, leukemias, lymphomas, multiple myelomas, prostate, gastric, breast, lung, and head and neck cancer [128][129][130][131][132][133][134].…”

Section: Activation Of Stat3mentioning

confidence: 99%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

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Identification of a Genetic Signature of Activated Signal Transducer and Activator of Transcription 3 in Human Tumors

Cited by 177 publications

References 35 publications

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

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

Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

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