Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

Abstract:

:Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Wu Y,Ma S,Xia Y,Lu Y,Xiao S,Cao Y,Zhuang S,Tan X,Fu Q,Xie L,Li Z,Yuan Z

doi

10.1038/cddis.2016.465

subject

Has Abstract

pub_date

2017-01-26 00:00:00

pages

e2570

issue

1

issn

2041-4889

pii

cddis2016465

journal_volume

8

pub_type

杂志文章
  • Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6.

    abstract::Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the spe...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2015.62

    authors: Schüll S,Günther SD,Brodesser S,Seeger JM,Tosetti B,Wiegmann K,Pongratz C,Diaz F,Witt A,Andree M,Brinkmann K,Krönke M,Wiesner RJ,Kashkar H

    更新日期:2015-03-12 00:00:00

  • Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage.

    abstract::Polo-like kinase 1 (PLK1) is an important mitotic kinase and its expression is tightly regulated in the cell cycle and in the DNA damage response. PLK1 expression is previously shown to be suppressed by p53 and/or p21. Here, we demonstrate that the CCAAT box in the PLK1 promoter is pivotal for p53/p21-mediated PLK1 re...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2013.527

    authors: Lin YC,Chen YN,Lin KF,Wang FF,Chou TY,Chen MY

    更新日期:2014-01-09 00:00:00

  • Aquaporin 3 maintains the stemness of CD133+ hepatocellular carcinoma cells by activating STAT3.

    abstract::An increasing interest in liver cancer stemness arises owing to its aggressive behavior and poor prognosis. CD133, a widely known liver cancer stem cell marker, plays critical roles in the maintenance of liver cancer stemness. Thus, exploring the regulatory mechanism of CD133 expression is significant. In the present ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1712-0

    authors: Wang Y,Wu G,Fu X,Xu S,Wang T,Zhang Q,Yang Y

    更新日期:2019-06-13 00:00:00

  • p53 cooperates with SIRT6 to regulate cardiolipin de novo biosynthesis.

    abstract::The tumor suppressor p53 has critical roles in regulating lipid metabolism, but whether and how p53 regulates cardiolipin (CL) de novo biosynthesis is unknown. Here, we report that p53 physically interacts with histone deacetylase SIRT6 in vitro and in vivo, and this interaction increases following palmitic acid (PA) ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-0984-0

    authors: Li M,Hou T,Gao T,Lu X,Yang Q,Zhu Q,Li Z,Liu C,Mu G,Liu G,Bao Y,Wen H,Wang L,Wang H,Zhao Y,Gu W,Yang Y,Zhu WG

    更新日期:2018-09-20 00:00:00

  • Ankrd2 is a modulator of NF-κB-mediated inflammatory responses during muscle differentiation.

    abstract::Adaptive responses of skeletal muscle regulate the nuclear shuttling of the sarcomeric protein Ankrd2 that can transduce different stimuli into specific adaptations by interacting with both structural and regulatory proteins. In a genome-wide expression study on Ankrd2-knockout or -overexpressing primary proliferating...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2013.525

    authors: Bean C,Verma NK,Yamamoto DL,Chemello F,Cenni V,Filomena MC,Chen J,Bang ML,Lanfranchi G

    更新日期:2014-01-16 00:00:00

  • Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor.

    abstract::Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1711-1

    authors: Zhang Z,Jiang D,Yang H,He Z,Liu X,Qin W,Li L,Wang C,Li Y,Li H,Xu H,Jin H,Qian Q

    更新日期:2019-06-17 00:00:00

  • miRNA let-7e targeting MMP9 is involved in adipose-derived stem cell differentiation toward epithelia.

    abstract::miRNA let-7e is involved in stem cell differentiation, and metalloproteinases are among its potential target genes. We hypothesized that the inhibitory action of let-7e on regulation of MMP9 expression could represent a crucial mechanism during differentiation of adipose-derived stem cells (ASCs). ASCs were differenti...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.2

    authors: Ventayol M,Viñas JL,Sola A,Jung M,Brüne B,Pi F,Mastora C,Hotter G

    更新日期:2014-02-06 00:00:00

  • Bmi1 regulates auditory hair cell survival by maintaining redox balance.

    abstract::Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we repor...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.549

    authors: Chen Y,Li L,Ni W,Zhang Y,Sun S,Miao D,Chai R,Li H

    更新日期:2015-01-22 00:00:00

  • Cryo-thermal therapy induces macrophage polarization for durable anti-tumor immunity.

    abstract::Many cancer therapies are being developed for the induction of durable anti-tumor immunity, especially for malignant tumors. The activation of antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), can bridge innate and adaptive immune responses against tumors. However, APCs have an immunosu...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1459-7

    authors: He K,Jia S,Lou Y,Liu P,Xu LX

    更新日期:2019-03-04 00:00:00

  • Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy.

    abstract::Hippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of a Yap heterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Müller glia. We first discovered an unexpected temporal dynamic of gene c...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-02860-9

    authors: Masson C,García-García D,Bitard J,Grellier ÉK,Roger JE,Perron M

    更新日期:2020-08-14 00:00:00

  • BRM270 inhibits cancer stem cell maintenance via microRNA regulation in chemoresistant A549 lung adenocarcinoma cells.

    abstract::Chemotherapy is a standard treatment for non-small-cell lung cancer (NSCLC). However, the dose-limiting toxicity of drugs and the development of chemoresistance are major clinical challenges to successful management of NSCLC. Asian traditional medicine is gaining global attention as a non-toxic alternative to chemothe...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-0277-7

    authors: Kwon T,Chandimali N,Huynh DL,Zhang JJ,Kim N,Bak Y,Yoon DY,Yu DY,Lee JC,Gera M,Ghosh M,Park YH,Jeong DK

    更新日期:2018-02-14 00:00:00

  • Tumor suppressor WWOX binds to ΔNp63α and sensitizes cancer cells to chemotherapy.

    abstract::The WWOX tumor suppressor is a WW domain-containing protein. Its function in the cell has been shown to be mediated, in part, by interacting with its partners through its first WW (WW1) domain. Here, we demonstrated that WWOX via WW1 domain interacts with p53 homolog, ΔNp63α. This protein-protein interaction stabilize...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2013.6

    authors: Salah Z,Bar-mag T,Kohn Y,Pichiorri F,Palumbo T,Melino G,Aqeilan RI

    更新日期:2013-01-31 00:00:00

  • Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvβ6 integrin in liver fibrosis.

    abstract::Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observe...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-2372-9

    authors: Xu T,Lu Z,Xiao Z,Liu F,Chen Y,Wang Z,Zhu S,Song Y

    更新日期:2020-03-23 00:00:00

  • MiR-29b controls fetal mouse neurogenesis by regulating ICAT-mediated Wnt/β-catenin signaling.

    abstract::β-Catenin has been widely implicated in the regulation of mammalian development and cellular homeostasis. However, the mechanisms by which Wnt/β-catenin signaling components regulate physiological events during brain development remain undetermined. Inactivation of glycogen synthase kinase (GSK)-3β leads to β-catenin ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.439

    authors: Shin J,Shin Y,Oh SM,Yang H,Yu WJ,Lee JP,Huh SO,Lee SH,Suh YH,Chung S,Kim HS

    更新日期:2014-10-16 00:00:00

  • Gamma-ray irradiation promotes premature meiosis of spontaneously differentiating testis-ova in the testis of p53-deficient medaka (Oryzias latipes).

    abstract::In this study, the roles of p53 in impaired spermatogenic male germ cells of p53-deficient medaka were investigated by analyzing histological changes, and gene expressions of 42Sp50, Oct 4 and vitellogenin (VTG2) by RT-PCR or in situ hybridization in the testes. We found that a small number of oocyte-like cells (testi...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2012.133

    authors: Yasuda T,Oda S,Li Z,Kimori Y,Kamei Y,Ishikawa T,Todo T,Mitani H

    更新日期:2012-10-04 00:00:00

  • VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells.

    abstract::Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and i...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-1015-x

    authors: Zhou K,Yao YL,He ZC,Chen C,Zhang XN,Yang KD,Liu YQ,Liu Q,Fu WJ,Chen YP,Niu Q,Ma QH,Zhou R,Yao XH,Zhang X,Cui YH,Bian XW,Shi Y,Ping YF

    更新日期:2018-09-24 00:00:00

  • HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway.

    abstract::Liver cancer is the second most common cause of cancer-related death worldwide. Approximately 70-90% of primary liver cancers are hepatocellular carcinoma (HCC). Currently, HCC patient prognosis is unsatisfactory due to high metastasis and/or post-surgical recurrence rates. Therefore, new therapeutic methods for inhib...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-018-0534-9

    authors: Chen L,Guo P,He Y,Chen Z,Chen L,Luo Y,Qi L,Liu Y,Wu Q,Cui Y,Fang F,Zhang X,Song T,Guo H

    更新日期:2018-05-01 00:00:00

  • Prolyl hydroxylase 2 silencing enhances the paracrine effects of mesenchymal stem cells on necrotizing enterocolitis in an NF-κB-dependent mechanism.

    abstract::Treatment options for necrotizing enterocolitis (NEC) remain inadequate. Here we examined if and how prolyl hydroxylase 2 (PHD2) silencing enhances the paracrine effects of bone-marrow-derived mesenchymal stem cells (BM-MSCs) on NEC. In this study, BM-MSCs were transduced with lentiviruses containing GFP (GFP-MSC) or ...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-2378-3

    authors: Chen H,Zhang H,Zheng Y,Min X,Luo Y,Zhou W,Ma F,Li J,Lu Q,Zhang C,Cai H,Sha W

    更新日期:2020-03-16 00:00:00

  • Functional validation of a human GLUD2 variant in a murine model of Parkinson's disease.

    abstract::Parkinson's disease (PD) is a common neurodegenerative disease characterized by Lewy body formation and progressive dopaminergic neuron death in the substantia nigra (SN). Genetic susceptibility is a strong risk factor for PD. Previously, a rare gain-of-function variant of GLUD2 glutamate dehydrogenase (T1492G) was re...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-03043-2

    authors: Zhang W,Gong J,Ding L,Zhang Z,Pan X,Chen X,Guo W,Zhang X,Yang X,Peng G,Lin Y,Gao F,Li Y,Zhu X,Xuan A,Wang S,Sun X,Zhang Y,Xu P

    更新日期:2020-10-22 00:00:00

  • Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress.

    abstract::Calcineurin signalling plays a critical role in the pathogenesis of many cardiovascular diseases. Calcineurin has been proven to affect a series of signalling pathways and to exert a proapoptotic effect in cardiomyocytes. However, whether it is able to regulate autophagy remains largely unknown. Here, we report that p...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2013.533

    authors: He H,Liu X,Lv L,Liang H,Leng B,Zhao D,Zhang Y,Du Z,Chen X,Li S,Lu Y,Shan H

    更新日期:2014-01-16 00:00:00

  • The cockayne syndrome B protein is essential for neuronal differentiation and neuritogenesis.

    abstract::Cockayne syndrome (CS) is a progressive developmental and neurodegenerative disorder resulting in premature death at childhood and cells derived from CS patients display DNA repair and transcriptional defects. CS is caused by mutations in csa and csb genes, and patients with csb mutation are more prevalent. A hallmark...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.228

    authors: Ciaffardini F,Nicolai S,Caputo M,Canu G,Paccosi E,Costantino M,Frontini M,Balajee AS,Proietti-De-Santis L

    更新日期:2014-05-29 00:00:00

  • MicroRNA-181a-5p and microRNA-181a-3p cooperatively restrict vascular inflammation and atherosclerosis.

    abstract::MicroRNAs have emerged as important post-transcriptional regulators of gene expression and are involved in diverse diseases and cellular process. Decreased expression of miR-181a has been observed in the patients with coronary artery disease, but its function and mechanism in atherogenesis is not clear. This study was...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-019-1599-9

    authors: Su Y,Yuan J,Zhang F,Lei Q,Zhang T,Li K,Guo J,Hong Y,Bu G,Lv X,Liang S,Ou J,Zhou J,Luo B,Shang J

    更新日期:2019-05-07 00:00:00

  • miR-6086 inhibits ovarian cancer angiogenesis by downregulating the OC2/VEGFA/EGFL6 axis.

    abstract::miRNAs have emerged as a pivotal component of gene regulatory networks, mediating cytokines secretion, cell cycle, and differentiation regulation. However, how miRNAs collaborate with transcription factors and downstream effector proteins that determine the fate of ovarian cancer cells remains to be understood, especi...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-2501-5

    authors: Wu B,Zhang L,Yu Y,Lu T,Zhang Y,Zhu W,Song Q,Lv C,Guo J,Tian Y,Deng N

    更新日期:2020-05-11 00:00:00

  • Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications.

    abstract::Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation a...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.591

    authors: Baldari S,Ubertini V,Garufi A,D'Orazi G,Bossi G

    更新日期:2015-01-29 00:00:00

  • 2,4,5-Trimethoxyldalbergiquinol promotes osteoblastic differentiation and mineralization via the BMP and Wnt/β-catenin pathway.

    abstract::Dalbergia odorifera has been traditionally used as a medicine to treat many diseases. However, the role of 2,4,5-trimethoxyldalbergiquinol (TMDQ) isolated and extracted from D. odorifera in osteoblast function and the underlying molecular mechanisms remain poorly understood. The aim of this study was to investigate th...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2015.185

    authors: Yun HM,Park KR,Quang TH,Oh H,Hong JT,Kim YC,Kim EC

    更新日期:2015-07-16 00:00:00

  • Preclinical studies using cisplatin/carboplatin to restore the Enzalutamide sensitivity via degrading the androgen receptor splicing variant 7 (ARv7) to further suppress Enzalutamide resistant prostate cancer.

    abstract::The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients' survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) sp...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-02970-4

    authors: Chou FJ,Lin C,Tian H,Lin W,You B,Lu J,Sahasrabudhe D,Huang CP,Yang V,Yeh S,Niu Y,Chang C

    更新日期:2020-11-02 00:00:00

  • Circulating microRNAs in breast cancer: novel diagnostic and prognostic biomarkers.

    abstract::Effective management of breast cancer depends on early diagnosis and proper monitoring of patients' response to therapy. However, these goals are difficult to achieve because of the lack of sensitive and specific biomarkers for early detection and for disease monitoring. Accumulating evidence in the past several years...

    journal_title:Cell death & disease

    pub_type: 杂志文章,评审

    doi:10.1038/cddis.2017.440

    authors: Hamam R,Hamam D,Alsaleh KA,Kassem M,Zaher W,Alfayez M,Aldahmash A,Alajez NM

    更新日期:2017-09-07 00:00:00

  • Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun.

    abstract::Mitogen-activated protein kinases (MAPKs) are conserved protein kinases that regulate a variety of important cellular signaling pathways. Among them, c-Jun N-terminal kinases (JNK) are known to be activated by various environmental stresses including virus infections. Previously, activation of the JNK pathway has been...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-017-0053-0

    authors: Fung TS,Liu DX

    更新日期:2017-12-13 00:00:00

  • Long non-coding RNA LRRC75A-AS1 facilitates triple negative breast cancer cell proliferation and invasion via functioning as a ceRNA to modulate BAALC.

    abstract::As a common female malignancy, triple-negative breast cancer (TNBC) is the most serious subtype in breast cancer (BC). BAALC binder of MAP3K1 and KLF4 (BAALC) is a common oncogene in acute myelocytic leukemia (AML). We sought to explore the role of BAALC in TNBC. In this study, BAALC was significantly upregulated in T...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/s41419-020-02821-2

    authors: Li S,Wu D,Jia H,Zhang Z

    更新日期:2020-08-18 00:00:00

  • Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism.

    abstract::Hyperoxia treatment has been known to induce neuronal and glial death in the developing central nervous system. Retinopathy of prematurity (ROP) is a devastating disease in premature infants and a major cause of childhood vision impairment. Studies indicate that, in addition to vascular injury, retinal neurons are als...

    journal_title:Cell death & disease

    pub_type: 杂志文章

    doi:10.1038/cddis.2014.23

    authors: Narayanan SP,Xu Z,Putluri N,Sreekumar A,Lemtalsi T,Caldwell RW,Caldwell RB

    更新日期:2014-02-20 00:00:00