Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue

Yuan, Zhiquan; Guan, Yingjie; Chatterjee, Devasis; Chin, Y. Eugene

doi:10.1126/science.1105166

Cited by 685 publications

(661 citation statements)

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“…4). It is possible that LIF may influence glial gene expression by enhancing the association between STAT3 and CBP, as previously reported 36 . Consistent with this hypothesis, ChIP analyses indicated that LIF enhanced the recruitment of CBP to the GFAP promoter, likely through STAT3C (Fig.…”

Section: A Positive Autoregulatory Loop Of the Jak-stat Machinerysupporting

confidence: 58%

“…6a). LIF stimulation further increased the activity of the promoter, potentially by increasing STAT1/3 serine phosphorylation or by recruiting more endogenous pSTAT1/3 or CBP to the transcriptional machinery 36 . Western blot analyses indicated that overexpression of STAT3C in 3-DIV E11 cortical NPCs increased the overall activity of the Jak-STAT machinery as reflected by increased tyrosine (Tyr701 or Tyr705) and serine (Ser727) phosphorylation of STAT1/3 as well as increased protein levels of STAT1 and receptor gp130 (Fig.…”

Section: A Positive Autoregulatory Loop Of the Jak-stat Machinerymentioning

confidence: 99%

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A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

et al. 2005

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During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokineinduced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.During embryonic development, the generation of three major neural cell types (neurons, astrocytes, and oligodendrocytes) in the CNS occurs sequentially, whereby almost all neurons are generated before the appearance of glial cells 1,2 , with the exception of a few COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2014 November 06. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sites of postnatal and adult neurogenesis such as the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the forebrain 3 . This strategy of building the CNS through sequential production of neurons and glia has become more comprehensible, as recent findings have demonstrated that glial cells are important in critical neuronal maturation processes such as axonal path finding and synapse formation [4][5][6] . It is conceivable that delayed or precocious production of glial cells may lead to inappropriate wiring, disorganization, and eventually, dysfunction of the CNS.The 'neurons-first, glia-second' differentiation theme for neural progenitors can be recapitulated in culture. Cortical neural progenitor stem cells isolated from relatively early embryonic stages (for example, mouse embryonic day (E) 10-11) give rise to neurons, not glial cells, after short-term culturing (fewer than 4 d), whereas cortical progenitors isolated from perinatal stages tend to differentiate into astrocytes under the same culture conditions 7 .In addition, both E10-11 cortical progenitors and embryonic stem cell-derived neural stem or progenitor cells (NSCs or NPCs) switch from being neurogenic to gliogenic over time in vitro 8,9 , suggesting that the molecular switch for the transition from neurogenesis to gliogenesis may be internally programmed in neural progenitors.S...

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Section: A Positive Autoregulatory Loop Of the Jak-stat Machinerysupporting

confidence: 58%

Section: A Positive Autoregulatory Loop Of the Jak-stat Machinerymentioning

confidence: 99%

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

et al. 2005

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“…A direct interaction of KAP1 with HDACs is also proposed to be a mechanism for transcriptional repression by KAP1 (Underhill et al, 2000;Satou et al, 2001;Schultz et al, 2001). It has also been demonstrated that STAT3 associates with HDAC3 and that trichostatin A, an HDAC inhibitor, restores its transcriptional activity (Yuan et al, 2005). We tested the effects of KAP1 on interactions between STAT3 and HDAC3.…”

Section: Interactions Between Stat3 and Kap1mentioning

confidence: 96%

Physical and functional interactions between STAT3 and KAP1

et al. 2007

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Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation and survival in immune responses, hematopoiesis, neurogenesis and other biological processes. For example, STAT3 has been reported to be constitutively activated in numerous cancer cells. To clarify the molecular mechanisms underlying the STAT activation, we performed yeast two-hybrid screening and identified KAP1/TIF1b as a novel STATbinding partner. KAP1 is a universal corepressor protein for the Kruppel-associated box zinc-finger protein superfamily of transcriptional repressors. We found endogenous KAP1 associated with endogenous STAT3 in vivo. Importantly, small-interfering RNA-mediated reduction of KAP1 expression enhanced interleukin (IL)-6-induced STAT3-dependent transcription and gene expression. Furthermore, reduction of KAP1 expression resulted in the marked accumulation of STAT3 phosphorylated on Ser727 in the nucleus, a modification that regulates its transcriptional activation. These results indicate that KAP1 may serve as a transcriptional regulator of the IL-6/STAT3 signaling pathway.

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“…As already described for some factors (STAT3 and BAX), reversibile acetylation affects the subcellular localization of several proteins. In some cases, the nuclear localization signal contains acetylatable lysine residues that favour nuclear retention when acetylated 23 . In the case of the multifunctional HMG box 1 (HMGB1) protein, acetylation favours nuclear export and cytosolic accumulation before secretion during inflammatory and/or necrotic processes 29 .…”

Section: At a Glancementioning

confidence: 99%

“…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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Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue

Cited by 685 publications

References 26 publications

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

Physical and functional interactions between STAT3 and KAP1

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

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