Activation of Stat3 Sequence-specific DNA Binding and Transcription by p300/CREB-binding Protein-mediated Acetylation

Wang, Rui; Cherukuri, Pratima; Luo, Jianyuan

doi:10.1074/jbc.m413930200

Cited by 247 publications

(213 citation statements)

References 36 publications

(36 reference statements)

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“…The major STAT3 acetylation site that enhances its DNA binding activity and transactivation activity is located at its C-terminal position lysine 685 [31] . The present study demonstrated a novel mechanism of fibrogenesis mediated by STAT3 acetylation that had not been previously reported in the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…Although the classical view of STAT3 activation focuses on the phosphorylation on tyrosine 705 (Tyr705) and serine 727 (ser727) [30] , recent studies have shown that acetylation on lysine 685 (Lys685) of STAT3 also plays a role in transactivation of target genes [31,32] . The reversible acetylation of STAT3 is regulated by the CREB-binding protein/p300 family of histone acetyltransferases and histone deacetylases (HDACs) [31,33] .…”

Section: Introductionmentioning

confidence: 99%

“…The reversible acetylation of STAT3 is regulated by the CREB-binding protein/p300 family of histone acetyltransferases and histone deacetylases (HDACs) [31,33] . Several HDACs have been reported to be involved in deacetylation of STAT3 [32,34] .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

Shen

Wang

et al. 2014

Acta Pharmacol Sin

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Aim: To explore the relationship between the signal transducer and activator of transcription 3 (STAT3) signaling and renal fibrosis. Methods: Rat renal tubular epithelial NRK-52E cells were treated with angiotensin II (Ang II), nicotinamide (an inhibitor of NAD + -dependent class III protein deacetylases, SIRT1-7), or resveratrol (an activator of SIRT1). Mice underwent unilateral ureteral obstruction (UUO) were used for in vivo studies. Renal interstitial fibrosis was observed with HE and Masson's trichrome staining. STAT3 acetylation and phosphorylation, fibronectin, collagen I, collagen IV, and α-smooth muscle actin (α-SMA) levels were examined using Western blotting. Results: Nicotinamide (0.625-10 mmol/L) dose-dependently increased STAT3 acetylation on Lys685 and phosphorylation on Tyr705 in NRK-52E cells, accompanied by accumulation of fibronectin and collagen IV. Ang II increased STAT3 phosphorylation on Tyr705 and the expression of fibronectin, collagen IV and α-SMA in the cells. Pretreatment with resveratrol (12.5 μmol/L) blocked Ang II-induced effects in the cells. UUO induced marked STAT3 phosphorylation, fibronectin, collagen IV and α-SMA accumulation, and renal interstitial fibrosis in the obstructed kidneys, which were significantly attenuated by daily administration of resveratrol (100 mg/kg). Conclusion: STAT3 acetylation plays an important role in activation of STAT3 signaling pathway and consequent renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

Shen

Wang

et al. 2014

Acta Pharmacol Sin

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“…Crif1 is an essential and specific transcriptional coactivator of STAT3 signalling In Crif1-null MEFs, the receptor-proximal events, tyrosine phosphorylation and dimerization of STAT3 and its nuclear translocation, occurred properly, whereas the DNA binding and transcriptional activities of STAT3 were abolished, suggesting that Crif1 might be involved in the transcription mediated by STAT3. STAT3 requires several transcriptional cofactors for the proper expression of target genes (Giraud et al, 2002;Wang et al, 2005). Histone-modifying cofactors (CBP/p300 and NcoA/SRC1a) potentiate the STAT3-mediated transcription by linking STAT3 to the basal transcriptional machinery, and directly acetylate STAT3 to enhance the sequence-specific DNA binding ability (Giraud et al, 2002;Wang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Crif1 is a novel transcriptional coactivator of STAT3

Kwon

Koo

Moon

et al. 2008

EMBO J

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Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor that performs a broad spectrum of biological functions in response to various stimuli. However, no specific coactivator that regulates the transcriptional activity of STAT3 has been identified. Here we report that CR6-interacting factor 1 (Crif1) is a specific transcriptional coactivator of STAT3, but not of STAT1 or STAT5a. Crif1 interacts with STAT3 and positively regulates its transcriptional activity. Crif1 À/À embryos were lethal around embryonic day 6.5, and manifested developmental arrest accompanied with defective proliferation and massive apoptosis. The expression of STAT3 target genes was markedly reduced in a Crif1 À/À blastocyst culture and in Oncostatin M-stimulated Crif1-deficient MEFs. Importantly, the key activities of constitutively active STAT3-C, such as transcription, DNA binding, and cellular transformation, were abolished in the Crif1-null MEFs, suggesting the essential role of Crif1 in the transcriptional activity of STAT3. Our results reveal that Crif1 is a novel and essential transcriptional coactivator of STAT3 that modulates its DNA binding ability, and shed light on the regulation of oncogenic STAT3.

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“…This confers either potentiation of transcriptional activity or destabilization of the enhanceosome and termination of the transcriptional response 22 . In the case of the transcription factor signal transducer and activator of transcription 3 (STAT3), which is activated by cytokine signalling, cytosolic acetylation triggers STAT3 dimerization and subsequent nuclear translocation 23,24 . Acetylation of hypoxia-inducible factor 1 (HIF1) by the ARD1 HAT apparently leads to increased association with the von Hippel-Lindau (VHL) ubiquitylation complex and proteasome-mediated degradation, which has a regulatory role in the cellular response to changes in oxygen availability and angiogenesis 25,26 .…”

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confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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Activation of Stat3 Sequence-specific DNA Binding and Transcription by p300/CREB-binding Protein-mediated Acetylation

Cited by 247 publications

References 36 publications

Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

Crif1 is a novel transcriptional coactivator of STAT3

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

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