The STATs of cancer — new molecular targets come of age

Yu, Hua; Jove, Richard

doi:10.1038/nrc1275

Cited by 2,066 publications

(2,115 citation statements)

References 111 publications

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“…In B-lymphocyte signaling, STAT activation can occur via BCR and Lyn. As demonstrated recently, Lyn could be another potential pharmacological target in the suppression of aberrant STATs activation that arises in many malignancies and autoimmune disorders (Sternberg and Gilliland, 2004;Yu and Jove, 2004).…”

Section: Discussionmentioning

confidence: 94%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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Engagement of the B-cell antigen receptor (BCR) initiated by the Src kinase Lyn triggers rapid signaling cascades, leading to proliferation, differentiation or growth arrest of B cells. The Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathway, activated through cytokine receptors, mediates similar responses. Hypothesizing that Src and JAK pathways engage in crosstalk in B-cell signaling, we studied wild-type and Lyn-null B-cell lines, which express BCR. We found that activated BCR results in tyrosine phosphorylation of JAK-STAT, which required Lyn. To confirm that STAT activation is not due to JAK, we cloned the chicken homologs of JAK1 and JAK2 and made their antisense constructs. In cells expressing antisense JAK1 and JAK2, tyrosine phosphorylation of STAT was not inhibited following BCR stimulation. Using activation loop-specific phosphotyrosine antibodies, we did not detect phospho-JAK1 and phospho-JAK2 after BCR stimulation. The JAK inhibitor AG490 did not inhibit the tyrosine phosphorylation of Lyn or STAT after BCR simulation. An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3. In an electrophoretic mobility shift assay, BCR stimulation led to enhanced DNA binding of the STAT3 in DT40, but not in the Lynnull cells. We conclude that BCR engagement activates the STAT pathway via Lyn, independent of JAK.

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Section: Discussionmentioning

confidence: 94%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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“…While Akt and Erk1/Erk2 are common downstream mediators of IGF-IR, there is limited data concerning activation of STAT proteins by IGF-IR (Takahashi et al, 1999;Zong et al, 2000;Zhang et al, 2006). STATs are a family of cytoplasmic transcription factors that typically mediate cytokine and growth factor signaling and in turn, regulate proliferation, apoptosis, differentiation and motility (Yu and Jove, 2004). Phosphorylation of STAT proteins results in dimerization followed by translocation into the nucleus where they bind to DNA and regulate gene transcription.…”

Section: Discussionmentioning

confidence: 99%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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Overexpression and hyperactivation of the type I insulinlike growth factor receptor (IGF-IR) has been observed in human breast tumor biopsies. In addition, in vitro studies indicate that overexpression of IGF-IR is sufficient to transform cells such as mouse embryo fibroblasts and this receptor promotes proliferation and survival in breast cancer cell lines. To fully understand the function of the IGF-IR in tumor initiation and progression, transgenic mice containing human IGF-IR under a doxycyclineinducible MMTV promoter system were generated. Administration of 2 mg/ml doxycycline in the animals' water supply beginning at 21 days of age resulted in elevated levels of IGF-IR in mammary epithelial cells as detected by Western blotting and immunohistochemistry. Whole mount analysis of 55-day-old mouse mammary glands revealed that IGF-IR overexpression significantly impaired ductal elongation. Moreover, histological analyses revealed multiple hyperplasic lesions in the mammary glands of these 55-day-old mice. The formation of palpable mammary tumors was evident at approximately 2 months of age and was associated with increased levels of IGF-IR signaling molecules including phosphorylated Akt, Erk1/Erk2 and STAT3. Therefore, these transgenic mice provide evidence that IGF-IR overexpression is sufficient to induce mammary epithelial hyperplasia and tumor formation in vivo and provide a model to further understand the function of IGF-IR in mammary epithelial transformation.

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“…Given that STAT3 becomes activated by many tyrosine kinases (Yu and Jove, 2004), that it is persistently activated in a large spectrum of malignancies and, finally, that it has a key role in oncogenesis (Yu and Jove, 2004;Ling and Arlinghaus, 2005;Wasik et al, 2009), STAT3 is in all likelihood directly responsible for HIF1a gene activation in various tumors. Indeed, STAT3 has been recently shown to induce HIF1a transcription in v-Srctransfected murine 3T3 fibroblasts and in a human melanoma cell line (Niu et al, 2008).…”

Section: Npm/alk-stat3 Pathway Induces Hif1a Expression M Marzec Et Almentioning

confidence: 99%

“…At present, NPM/ALK represents a much more feasible target, given the proven effectiveness of kinase inhibitors in general and the beneficial impact of NPM/ALK inhibition already documented in preclinical models (Marzec et al, 2005;Galkin et al, 2007;Lu et al, 2009). Although STAT3 clearly represents a highly attractive therapeutic target in ALK þ TCL and many other types of cancer (Yu and Jove, 2004;Wasik et al, 2009), the compounds capable of inhibiting STAT3 activation developed so far still suffer from a lack of specificity and, often, toxicity (Yue and Turkson, 2009). Finally, considering that HIF1a expression has been shown to adversely affect the sensitivity of malignant cells to chemotherapeutic agents, it could be argued that the combination of an ALK inhibitor or, prospectively, a STAT3 inhibitor with these standard therapeutic agents should improve treatment outcome in ALK þ TCL and possibly other ALK-and STAT3-driven malignancies.…”

Section: Npm/alk-stat3 Pathway Induces Hif1a Expression M Marzec Et Almentioning

confidence: 99%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

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The STATs of cancer — new molecular targets come of age

Cited by 2,066 publications

References 111 publications

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

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