Loss of NECL1, a novel tumor suppressor, can be restored in glioma by HDAC inhibitor‐Trichostatin A through Sp1 binding site

Gao, Jing; Chen, Tao; Liu, Jin; Liu, Wei; Hu, Guangyu; Guo, Xinwen; Yin, Bin; Gong, Yanhua; Zhao, Jizong; Qiang, Boqin; Yuan, Jing; Peng, Xiaozhong

doi:10.1002/glia.20823

Cited by 38 publications

(24 citation statements)

References 43 publications

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“…Several studies have shown interactions of Sp1 with a variety of proteins, including p107, class I HDACs (HDAC1, HDAC2, and HDAC6), p300, and CBP (20,24,25,28,34,53,61). Modulation of the interactions between Sp1 and these partner proteins has been shown to be crucial for the regulation of Sp1-dependent gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that corepressors such as HDAC1, HDAC2, and HDAC6 may be recruited by Sp1 to repress gene expression (7,9,25,34). On the other hand, coactivators such as p300 and CBP also could be recruited by Sp1 to the promoters to transactivate gene expression (20,28). We sought to determine which corepressors or coactivators interact with Sp1.…”

Section: Fig 4 Dna Binding Ability Of Sp1 Is Essential For Zp Activmentioning

confidence: 99%

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Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai

Lin

Weng

et al. 2011

J Virol

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Epstein-Barr virus (EBV) undergoes latent and lytic replication cycles, and its reactivation from latency to lytic replication is initiated by expression of the two viral immediate-early transactivators, Zta and Rta. In vitro, reactivation of EBV can be induced by anti-immunoglobulin, tetradecanoyl phorbol acetate, and histone deacetylase inhibitor (HDACi). We have discovered that protein kinase C delta (PKC␦) is required specifically for EBV reactivation by HDACi. Overexpression of PKC␦ is sufficient to induce the activity of the Zta promoter (Zp) but not of the Rta promoter (Rp). Deletion analysis revealed that the ZID element of Zp is important for PKC␦ activation. Moreover, the Sp1 putative sequence on ZID is essential for PKC␦-induced Zp activity, and the physiological binding of Sp1 on ZID has been confirmed. After HDACi treatment, activated PKC␦ can phosphorylate Sp1 at serine residues and might result in dissociation of the HDAC2 repressor from ZID. HDACi-mediated HDAC2-Sp1 dissociation can be inhibited by the PKC␦ inhibitor, Rotterlin. Furthermore, overexpression of HDAC2 can suppress the HDACi-induced Zp activity. Consequently, we hypothesize that HDACi induces PKC␦ activation, causing phosphorylation of Sp1, and that the interplay between PKC␦ and Sp1 results in the release of HDAC2 repressor from Zp and initiation of Zta expression.Epstein-Barr virus (EBV), a human oncogenic virus, infects two types of human cells predominantly, B lymphocytes and epithelial cells, and EBV infection also is associated with an array of malignancies derived from these two cell types, including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma (49). Being a human gammaherpesvirus, EBV undergoes two cycles: latency and lytic replication. Although most latent products are important for its ability to immortalize cells, and the virus is present in a latent form in most EBV-associated cancer tissues, serological studies revealed that elevated antibody titers against some lytic antigens, or increased viral DNA load in serum, are risk factors for tumor development (8,33). In addition, experiments using the SCID mouse model suggested that Zta, an EBV lytic transactivator, is crucial for tumor formation (43). In vitro, experimental approaches also revealed that EBV lytic products may contribute to the pathogenesis of EBV-associated diseases, via upregulation of cytokines, cell growth factors or antiapoptotic proteins (5, 48, 50). Thus, the reactivation of EBV not only leads to the production of viral progeny but also facilitates viral pathogenesis.In vitro, EBV persists predominantly in a latent form in host cells. However, lytic replication can be elicited conditionally by many different chemicals and physical stimuli or by ectopic transfection with two transactivators, Zta or Rta (49). These inducing agents provide the best available models for the study of essential factors involved in the switch of EBV from latency to lytic replication. Tetradecanoyl phorbol acetate (TPA) and anti-Ig are...

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Section: Discussionmentioning

confidence: 99%

Section: Fig 4 Dna Binding Ability Of Sp1 Is Essential For Zp Activmentioning

confidence: 99%

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai

Lin

Weng

et al. 2011

J Virol

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“…In this complex, Smad2/3 has been reported to interact directly with both SP1 and p300 [44]. Although no direct interaction between SP1 and p300 has been reported at the COL1A2 promoter, a recent study demonstrated that SP1 binds p300 and recruits it for NECL1 transcription [45]. Since bortezomib did not prevent Smad2 binding to COL1A2 , it can be hypothesized that it affects SP1 directly or perturbs in a more subtle manner the interactions of SP1 with Smad2/3 or p300.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of matrix metalloproteinase-1 and collagen 1A2 explains the anti-fibrotic effect exerted by proteasome inhibition in human dermal fibroblasts

et al. 2010

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IntroductionExtracellular matrix (ECM) turnover is controlled by the synthetic rate of matrix proteins, including type I collagen, and their enzymatic degradation by matrix metalloproteinases (MMPs). Fibrosis is characterized by an unbalanced accumulation of ECM leading to organ dysfunction as observed in systemic sclerosis. We previously reported that proteasome inhibition (PI) in vitro decreases type I collagen and enhances MMP-1 production by human fibroblasts, thus favoring an antifibrotic fibroblast phenotype. These effects were dominant over the pro-fibrotic phenotype induced by transforming growth factor (TGF)-β. Here we investigate the molecular events responsible for the anti-fibrotic phenotype induced in fibroblasts by the proteasome inhibitor bortezomib.MethodsThe steady-state mRNA levels of COL1A1, COL1A2, TIMP-1, MMP-1, and MMP-2 were assessed by quantitative PCR in human dermal fibroblasts cultured in the presence of TGF-β, bortezomib, or both. Transient fibroblast transfection was performed with wild-type and mutated COL1A1 and MMP-1 promoters. Chromatin immunoprecipitation, electrophoretic mobility shift assay (EMSA), and DNA pull-down assays were used to assess the binding of c-Jun, SP1, AP2, and Smad2 transcription factors. Immunoblotting and immunofluorescent microscopy were performed for identifying phosphorylated transcription factors and their cellular localization.ResultsBortezomib decreased the steady-state mRNA levels of COL1A1 and COL1A2, and abrogated SP1 binding to the promoter of COL1A2 in both untreated and TGF-β-activated fibroblasts. Reduced COL1A2 expression was not due to altered TGF-β-induced Smad2 phosphorylation, nuclear translocation, or binding to the COL1A2 promoter. In contrast to collagen, bortezomib specifically increased the steady-state mRNA levels of MMP-1 and enhanced the binding of c-Jun to the promoter of MMP-1. Furthermore, disruption of the proximal AP-1-binding site in the promoter of MMP-1 severely impaired MMP-1 transcription in response to bortezomib.ConclusionsBy altering the binding of at least two transcription factors, c-Jun and SP1, proteasome inhibition results in increased production of MMP-1 and decreased synthesis of type I collagen in human dermal fibroblasts. Thus, the antifibrotic phenotype observed in fibroblasts submitted to proteasome inhibition results from profound modifications in the binding of key transcription factors. This provides a novel rationale for assessing the potential of drugs targeting the proteasome for their anti-fibrotic properties.

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“…A corollary strong tumor-suppressive effect was demonstrated in xenografts of human tumors (Figures 4, 5, and 6). This effect is caused probably by a significant increase in an entire set of tumor suppressors, some of them like the brain-specific protein cell adhesion molecule 3 (CADM3) (Gao et al, 2009), was found inactivated in glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth

Kravtsova‐Ivantsiv

Shomer

Cohen-Kaplan

et al. 2015

Cell

108

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NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.

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Loss of NECL1, a novel tumor suppressor, can be restored in glioma by HDAC inhibitor‐Trichostatin A through Sp1 binding site

Cited by 38 publications

References 43 publications

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Transcriptional regulation of matrix metalloproteinase-1 and collagen 1A2 explains the anti-fibrotic effect exerted by proteasome inhibition in human dermal fibroblasts

KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth

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