Structure, function, and regulation of STAT proteins

Lim, Cheh Peng; Cao, Xinmin

doi:10.1039/b606246f

Cited by 283 publications

(255 citation statements)

References 191 publications

(271 reference statements)

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“…3Ciii–3Cv, blue and red, respectively). There is wealth of evidence that in response to upstream cytokines and growth factors, including IL6, CNTF, IL1β, and PDGF, both JAK and MAPK kinases induce STAT3 transcriptional activity by phosphorylating STAT3 on its tyrosine 705 and serine 727 residue, respectively 23, 26. Phosphorylated STAT3 dimers migrate into the nucleus and transcribe target genes, such as GFAP 27 and CxCl10 28.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

et al. 2015

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A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long‐term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM‐MSCs) to help identify factors able to modulate graft‐induced reactive gliosis. We found in vivo that intravitreal BM‐MSC transplantation is associated with gliosis‐mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin‐2 (Lcn‐2) was identified as a potential new indicator of graft‐induced reactive gliosis. Pharmacological inhibition of STAT3 in BM‐MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM‐MSC retinal engraftment. Inhibition of stem cell‐induced reactive gliosis is critical for successful transplantation‐based strategies for neuroprotection, replacement, and regeneration of the optic nerve. Stem Cells 2015;33:3006–3016

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Section: Resultsmentioning

confidence: 99%

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

et al. 2015

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“…STAT proteins are activated by a plethora of cytokines, including interferons and interleukins, as well as growth factors and hormones (Lim and Cao 2006) and the relevance of the STAT pathways in the response to cytokines and inflammation is widely known. In the mouse model of NO-induced nociceptive behavior we observed a dramatic increase in the expression of the phosphorylated form of STAT1 (pSTAT1) following NO donors' injection within PAG and thalamus with a time-course consistent with the nociceptive behavior.…”

Section: Discussionmentioning

confidence: 99%

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Galeotti¹,

Ghelardini²

2012

Psychopharmacology

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Rationale Hypericum perforatum, popularly called St. John's wort (SJW), is a medicinal plant mainly used as antidepressant with a favorable safety profile than standard antidepressants. Some studies have also documented other SJW bioactivities, including pain modulation. Objectives The aim of this study was to demonstrate the capability of SJW to relieve nitric oxide (NO)-induced nociceptive hypersensitivity and identify the effective component. Methods Nociceptive hypersensitivity induced by administration of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) was assessed by cold and hot plate tests. The cellular pathways and molecular targets involved were investigated by Western blotting. Results GTN and SNP produced a prolonged allodynia and hyperalgesia in mice. A single oral administration of low doses of an SJW dried extract or purified hypericin reversed the NO donor-induced nociceptive behavior whereas hyperforin and flavoinoids were ineffective. Investigating into the cellular pathways involved, an increased CREB and STAT1 phosphorylation, and activation of NF-κB were detected within PAG and thalamus following NO donors' administration. These cellular events were prevented by SJW or hypericin. Since hypericin showed PKC blocking properties, a role of PKC as an upstream modulator of these transcription factors was hypothesized. NO donors increased expression and phosphorylation of protein kinase C (PKC) γ and ε isoforms, molecular events prevented by SJW or hypericin. Conclusions SJW reversed NO-induced nociceptive hypersensitivity through the blockade of a supraspinal signaling pathway involving a PKC-dependent CREB, STAT1 and NF-κB activation due to presence of hypericin. These data indicate SJW/hypericin as a therapeutic perspective for pain treatment.

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“…CXCR4 and JAK2/STAT3 signalling in SCLC M Pfeiffer et al diseases (Levine and Gilliland, 2007), and constitutively phosphorylated STAT3 is found in many solid tumours and haematopoietic malignancies (Lim and Cao, 2006). The chemokine receptor CXCR4 was described to activate the JAK2/STAT3 pathway in different cell lines (Vila-Coro et al, 1999;Soriano et al, 2003;Opdam et al, 2004;Moriguchi et al, 2005) and the intracellular domains responsible for JAK2 binding have been discovered by mutational analysis (Ahr et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

et al. 2009

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Small cell lung cancer (SCLC) is an aggressive, rapidly metastasising tumour. Previously, we demonstrated the influence of CXCL12 -CXCR4 interaction on processes involved in metastasis and chemoresistance in SCLC. We show here that STAT3 is expressed in both primary SCLC tumour tissues and SCLC cell lines. We investigated the function of STAT3 upon CXCL12 stimulation in SCLC cell lines. Small cell lung cancer cell lines present constitutive phosphorylation of STAT3, and in the reference cell lines NCI-H69 and NCI-H82 constitutive phosphorylation was further increased by CXCL12 stimulation. Further investigating this signalling cascade, we showed that it involves interactions between CXCR4 and JAK2 in both cell lines. However CXCL12-induced adhesion to VCAM-1 could be completely inhibited by the JAK2 inhibitor AG490 only in NCI-H82. Furthermore, CXCR4 antagonist but not AG490 inhibited cell adhesion whereas both antagonisms were shown to inhibit growth of the cells in soft agar, indicating the central involvement of this signalling in anchorage-independent growth of SCLC cells. Most interestingly, while using primary tumour material, we observed that in contrast to non-small-cell lung cancer samples from primary tumour tissues, all analysed samples from SCLC were strongly positive for tyrosine-phosphorylated STAT3. Taken together, these data indicate that STAT3 is constitutively phosphorylated in SCLC and is important in SCLC growth and spreading thus presenting an interesting target for therapy.

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Structure, function, and regulation of STAT proteins

Cited by 283 publications

References 191 publications

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

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