Activation of STAT proteins and growth control

Bromberg, Jacqueline

doi:10.1002/1521-1878(200102)23:2<161::aid-bies1023>3.0.co;2-0

Cited by 266 publications

(210 citation statements)

References 80 publications

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“…Control crosses were carried out by crossing hop Tum-l /FM7 females to males of wild-type or stocks bearing different 'marker' genes, such as Oregon R, Canton S, w 1118 and y 1 . The mean TI of the hop Tum-l/+ F1 progeny from these crosses was 0.39 ± 0.11.…”

Section: Fly Stocks and Geneticsmentioning

confidence: 99%

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JAK signaling globally counteracts heterochromatic gene silencing

et al. 2006

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The JAK/STAT pathway has pleiotropic roles in animal development, and its aberrant activation is implicated in multiple human cancers [1][2][3] . JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation or survival. We show here in a Drosophila melanogaster hematopoietic tumor model, however, that JAK overactivation globally disrupts heterochromatic gene silencing, an epigenetic tumor suppressive mechanism 4 . This disruption allows derepression of genes that are not direct targets of STAT, as evidenced by suppression of heterochromatin-mediated position effect variegation. Moreover, mutations in the genes encoding heterochromatin components heterochromatin protein 1 (HP1) and Su(var)3-9 enhance tumorigenesis induced by an oncogenic JAK kinase without affecting JAK/STAT signaling. Consistently, JAK loss of function enhances heterochromatic gene silencing, whereas overexpressing HP1 suppresses oncogenic JAK-induced tumors. These results demonstrate that the JAK/STAT pathway regulates cellular epigenetic status and that globally disrupting heterochromatin-mediated tumor suppression is essential for tumorigenesis induced by JAK overactivation.The D. melanogaster genome contains a single JAK, named Hopscotch (Hop), and a single STAT, STAT92E, that are most similar to JAK2 and STAT5, respectively [5][6][7] . Hop and STAT92E function in a canonical JAK/STAT pathway, mediating cell proliferation, differentiation and migration in a variety of developmental processes [7][8][9] . Tumorous-lethal (Tum-l) is an oncogenic allele of hop and encodes a hyperactive JAK kinase due to a G341E substitution [10][11][12] . hop Tum-l is associated with high incidence of hematopoietic tumors in heterozygous animals, a leukemia-like phenotype. These tumors manifest as melanotic masses of blood cell aggregates in the larval or adult body cavity, resulting from overproliferation and differentiation of particular blood cell types 10,11 . It has been shown that Tum-l induces hematopoietic tumors by overactivating STAT92E, as STAT92E is hyperphosphorylated by Hop Tum-l , and that reducing the gene dosage of STAT92E suppresses Tum-l tumorigenicity 5,6,13 . Classical genetic screens and genome-wide RNA interference (RNAi) analyses in D. melanogaster have led to the identification of many components involved in the JAK/STAT pathway or in its modulation 5,6,[13][14][15] . However, as Author Contributions: The initial Df screen was performed by H.C.C., J.L. and L.L.; identification of modifier genes and phenotype assessment were performed by S.S.; F.X. contributed to the protein blot analysis. W.X.L. designed the study and wrote the paper. Competing Interests Statement:The authors declare that they have no competing financial interests. In order to understand how overactivation of the JAK/STAT pathway causes hematopoietic tumors, we undertook a genetic screen to identify genes important for the tumorigenicity of hop Tum-l . We first...

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Section: Fly Stocks and Geneticsmentioning

confidence: 99%

“…

AbstractThe JAK/STAT pathway has pleiotropic roles in animal development, and its aberrant activation is implicated in multiple human cancers [1][2][3] . JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation or survival.

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mentioning

confidence: 99%

JAK signaling globally counteracts heterochromatic gene silencing

et al. 2006

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“…Under normal conditions and during development, the activation of STATs is transient and upregulation of gene transcription is strictly regulated. However, emerging evidence supports the idea that some STATs play an important role in oncogenesis: STAT3, in particular, is often activated in leukemia, lymphoma, and breast, lung, and prostate cancer (Bowman et al, 2000;Bromberg, 2001Bromberg, , 2002. Furthermore, it was shown that dominantnegative STAT3 mutants block oncogenic transformation, whereas constitutively activated STAT3 mutants can induce it (Bromberg et al, 1999).…”

Section: Introductionmentioning

confidence: 96%

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

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“…STATs are activated by ligand-bindings to specific cell surface receptors, and after tyrosine phosphorylation, dimerization and translocation to the nucleus, directly regulate target genes (Darnell, 1997;Bromberg, 2001). It has been shown that aberrant expression of STAT involves in cell transformation and tumor formation (O'Shea et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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Signal transducers and activators of transcription (STATs) are latent transcription factors that mediate cytokine-and growth factor-induced transcription. Constitutive activation of STAT3 has been shown in human cancers and transformed cell lines. We report that STAT3, but not STAT1 and STAT5, becomes phosphorylated in response to epidermal growth factor (EGF) and achieves maximal induction of collagenase-1 (MMP-1) transcription by interacting with c-JUN. Phosphorylation of STAT3 protein is biphasic: the first peak within 30 min and the second peak between 4 and 8 h. Association of STAT3 with c-JUN is detected and its constituting STAT3 is increasingly phosphorylated. The STAT and AP-1 elements are necessary for effective induction of MMP-1 promoter by EGF. Mutation of AP-1 element closely located at the STAT site abolishes the binding not only of c-JUN but also of STAT3 to MMP-1 promoter, resulting in the loss of the responsiveness to EGF. By blocking STAT3 activity with the dominant-negative form, we show the requirement of STAT3 for EGF induction of MMP-1 and MMP-10 (stromelysin-2). Furthermore, expression of the dominant-negative STAT3 is sufficient to inhibit the constitutive and EGF-inducible cell migration and invasion and the tumor formation in nude mice. These results demonstrate that STAT3 phosphorylation and its possible interaction with c-JUN are required for the strong responsiveness of MMP-1 to EGF, and STAT3 activation is crucial for exhibition of malignant characteristics in T24 bladder cancer cells.

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Activation of STAT proteins and growth control

Cited by 266 publications

References 80 publications

JAK signaling globally counteracts heterochromatic gene silencing

JAK signaling globally counteracts heterochromatic gene silencing

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

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

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