Activation of Stat3 in v-Src-transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity

Zhang, Yi; Turkson, James; Carter‐Su, Christin; Smithgall, Thomas E.; Levitzki, Alexander; Kraker, Alan J.; Krolewski, John J.; Medveczky, Peter G.; Jove, Richard

doi:10.1074/jbc.m002383200

Cited by 153 publications

(142 citation statements)

References 56 publications

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“…Several other kinases have been implicated in the phosphorylation of STAT3, including members of the Src family (hck, src), Erb2, anaplastic lymphoma kinase, protein kinase C-␦, c-fes, and epidermal growth factor receptor (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). Whether any of these kinases are active in MM cells, and which of these kinases is activated by IL-6, is not fully known.…”

Section: Discussionmentioning

confidence: 99%

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Bharti

Donato

Aggarwal

2003

The Journal of Immunology

478

304

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Numerous reports suggest that IL-6 promotes survival and proliferation of multiple myeloma (MM) cells through the phosphorylation of a cell signaling protein, STAT3. Thus, agents that suppress STAT3 phosphorylation have potential for the treatment of MM. In the present report, we demonstrate that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited IL-6–induced STAT3 phosphorylation and consequent STAT3 nuclear translocation. Curcumin had no effect on STAT5 phosphorylation, but inhibited the IFN-α-induced STAT1 phosphorylation. The constitutive phosphorylation of STAT3 found in certain MM cells was also abrogated by treatment with curcumin. Curcumin-induced inhibition of STAT3 phosphorylation was reversible. Compared with AG490, a well-characterized Janus kinase 2 inhibitor, curcumin was a more rapid (30 min vs 8 h) and more potent (10 μM vs 100 μM) inhibitor of STAT3 phosphorylation. In a similar manner, the dose of curcumin completely suppressed proliferation of MM cells; the same dose of AG490 had no effect. In contrast, a cell-permeable STAT3 inhibitor peptide that can inhibit the STAT3 phosphorylation mediated by Src blocked the constitutive phosphorylation of STAT3 and also suppressed the growth of myeloma cells. TNF-α and lymphotoxin also induced the proliferation of MM cells, but through a mechanism independent of STAT3 phosphorylation. In addition, dexamethasone-resistant MM cells were found to be sensitive to curcumin. Overall, our results demonstrated that curcumin was a potent inhibitor of STAT3 phosphorylation, and this plays a role in the suppression of MM proliferation.

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Section: Discussionmentioning

confidence: 99%

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Bharti

Donato

Aggarwal

2003

The Journal of Immunology

478

304

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“…Furthermore, v-Src was shown to activate not only the tyrosine phosphorylation of STAT3 but also DNA binding, and transcriptional activation (Cao et al, 1996). Although there are numerous studies, which demonstrate that the kinase activity of JAK is not required for STAT3 activation, the JAK protein may still play a role in recruiting STAT3 to the Src complex (Zhang et al, 2000). Most importantly, a number of studies demonstrated not only that the full oncogenic activity of v-Src depended on STAT3, but that STAT3 activation was required for vSrc transformation (Bromberg et al, 1998;Turkson et al, 1998;Odajima et al, 2000).…”

Section: Stats As a Mediator Of Sfk-induced Transformationmentioning

confidence: 99%

Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis

2004

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“…In different experimental models tumorigenesis is associated with increased expression and/or activity of JAK1, 2 [27,28] or STAT3, 5 [29] . A constitutively active mutant of STAT3 has been shown to transform rat fibroblasts [30] , and the increased expression of wild type STAT5 in the lymphoid lineage induced T cell leukemia in mice [31] .…”

Section: Jak-stat Signaling and Carcinogenesismentioning

confidence: 99%

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

Smirnova¹

2007

WJG

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The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.

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Activation of Stat3 in v-Src-transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity

Cited by 153 publications

References 56 publications

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

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