CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1

Hu, Xuebin; Lu, Zhaojing; Yu, Shanshan; Reilly, James; Liu, Fei; Jia, Danna; Qin, Yayun; Han, Shanshan; Gao, Liang; Qu, Zhen; Lv, Yuexia; Li, Jingzhen; Huang, Yu-Wen; Jiang, Tao; Jia, Haibo; Wang, Qing Kenneth; Liu, Jingyu; Shu, Xinhua; Tang, Zhaohui; Liu, Mugen

doi:10.1080/15548627.2018.1520548

Cited by 51 publications

(51 citation statements)

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“…Previous study shows FoxO1 and FoxO3 deletion exhibit more severity cartilage degradation than FoxO4 [29,31,32], which suggested that FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and OA. By using C28 cell lines, it is con rmed that ATG7, FoxO1 and SIRT1 have an apparent interaction, which is supported by precious studies in other organs [14,33,34]. Our study demonstrated that Sirt1 regulated FoxO1 transcriptional activity, and then FoxO1 mediated autophagy to maintain cartilage homeostasis via cartilage hypertrophy and apoptosis.…”

Section: Discussionsupporting

confidence: 77%

Sirt1 Protects Cartilage Against Degradation through FoxO1 Nucleo-cytoplasmic Shuttling and Positive Regulation of Autophagy

Zhang

Gào

et al. 2020

Preprint

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Background: Sirt1 plays an important role in the pathophysiological process of osteoarthritis (OA) as we reported previously, however, the underlying mechanisms are still poorly addressed. Methods: The cartilage samples from OA patients’ knee joint were collected and detected histologically and immunohistochemistically. The effects of cartilage specific Sirt1 deletion on cartilage homeostasis were evaluated in destabilization of medial meniscus (DMM)-induced OA mice model (n=10). Finally, the underlying regulation of Sirt1 on cartilage was verified by coimmunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) in vitro.Results: The expression levels of SIRT1, FoxO1 and autophagy decreased in OA cartilage. We further found that DMM-induced OA in cartilage specific Sirt1 deletion mice displayed an aggravated OA development, with increased chondrocytes hypertrophy and apoptosis while decreased autophagy activity. In vitro experiments indicated that FoxO1 regulated Sirt1 expression by nucleo-cytoplasmic shuttling through an auto-feedback loop leading to an increased autophagy level. Consistently, the activation of autophagy activity partly rescued OA-like changes in chondrocytes.Conclusions: Sirt1 protects cartilage against degradation through FoxO1 nucleo-cytoplasmic shuttling and positive regulation of autophagy, which all play a protective role in OA pathophysiological process, possibly partial adjustment by positive feedback.

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Section: Discussionsupporting

confidence: 77%

Sirt1 Protects Cartilage Against Degradation through FoxO1 Nucleo-cytoplasmic Shuttling and Positive Regulation of Autophagy

Zhang

Gào

et al. 2020

Preprint

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“…In fact, it was of our interest first to determine the upstream regulator induced by RES. Currently, it is well established that a bidirectional coordinated positive amplification loop exists between SIRT1 and AMPK 40,41 and between AMPK and Akt. 42,43 In addition, SIRT1…”

Section: Sirt1 Is Located Upstream Ampk and Akt Through Treatment Wmentioning

confidence: 99%

Resveratrol protects against cadmium chloride‐induced hippocampal neurotoxicity by inhibiting ER stress and GAAD 153 and activating sirtuin 1/AMPK/Akt

Shati

2019

Environmental Toxicology

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This study investigated whether the apoptotic effect induced by cadmium chloride (CdCl2) in rat's hippocampi and neuroprotection afforded by resveratrol (RES) are mediated by modulation of ER stress and involve sirtuin 1 (SIRT1)/AMPK/Akt axis. Adult male Wistar rats were divided into four groups (n = 24/group) as control, control + RES (300 mg/kg), CdCl2 (5 mg/kg), and CdCl2 + RES. All treatments were conducted orally for 45 days. Also, cultured hippocampal cells were treated with CdCl2 in the presence or absence of RES and with or without preincubation with SIRT1, AMPK, or PI3K inhibitors. CdCl2 impaired retention and spatial memories of rats and reduced levels and activities of SIRT1 and inhibited AMPK/Akt axis in their hippocamapi where SIRT1 was the upstream regulator. It also enahnced hippocampal levels of reactive oxygen species (ROS) and expression of caspase‐12 and caspase‐3, depleted glutathione (GSH) levels, and activated GRP78, activating transcription factor‐6, GAAD 153, X‐box binding protein‐1 arms of ER stress. On the contrary, RES coadminsitration completley abolished all these events. Interstingly and in control rats, RES not only increased levels of GSH, but also enhenced protein levels of B‐cell lymphoma 2 (Bcl‐2) and dwonregulated GAAD 153. In both control and CdCl2‐treated rats, pharmacological inhibtion of SIRT1, AMPK, and Akt compleltely abolished all effects afforded by RES. In conclusion, CdCl2‐induced hippocampal apopotis is associated with reduction of SIRT1/AMPK/Akt activity levels, ROS generation, downregulation of Bcl‐2, and activities, activation of ER stress, and GAAD 153, whereas RES is able to reverse these effects through activation of SIRT1/AMPK/Akt.

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“…7A). LCB4/5 homologs that were UES in PharmacoDB included: (1) CERKL ( Additional File 8, Files B-C; 1-0-6 ), a ceramide kinase like gene that regulates autophagy by stabilizing SIRT1 [264], a gene mentioned above for its inhibition being synergistic with cytarabine against acute lymphoblastic leukemia cells [138], and (2) AGK , which is overexpressed in hepatocellular carcinoma, glioma, breast, and cervical squamous cell cancers [265-268]. Two stronger interaction modules, evidenced by deletion enhancement for both the K and L CPPs, were protein localization to septin ring (HSL1 and ELM1 ) and the Sec61 translocon complex ( SBH1, SBH2 , and SEC61 ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

Santos

Icyuz

Pound

et al. 2019

Preprint

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10Knowledge about synthetic lethality can be applied to enhance the efficacy of 11 anti-cancer therapies in individual patients harboring genetic alterations in their cancer 12 that specifically render it vulnerable. We investigated the potential for high-resolution 13 phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, 14 comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine 15 and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures 16 yet distinct anti-tumor efficacy. Human deoxycytidine kinase (dCK) was conditionally 17 expressed in the S. cerevisiae genomic library of knockout and knockdown (YKO/KD) 18 strains, to globally and quantitatively characterize differential drug-gene interaction for 19 gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, 20 histone modification, chromatin remodeling, and apoptosis-related processes influence 21 gemcitabine specifically, while drug-gene interaction specific to cytarabine was less 22 enriched in Gene Ontology. Processes having influence over both drugs were DNA 23 repair and integrity checkpoints and vesicle transport and fusion. Non-GO-enriched 24 genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics 25 data were integrated to identify yeast-human homologs with correlated differential gene 26 2 expression and drug-efficacy, thus providing a unique resource to predict whether 27 differential gene expression observed in cancer genetic profiles are causal in tumor-28 specific responses to cytotoxic agents. 29 30 Keywords: 31 yeast phenomics, gene-drug interaction, genetic buffering, quantitative high 32 throughput cell array phenotyping (Q-HTCP), cell proliferation parameters (CPPs), 33 gemcitabine, cytarabine, recursive expectation-maximization clustering (REMc), 34 pharmacogenomics 35 36 Introduction: 37Genomics has enabled targeted therapy aimed at cancer driver genes and 38 oncogenic addiction [1], yet traditional cytotoxic chemotherapeutic agents remain among 39 the most widely used and efficacious anti-cancer therapies [2]. Changes in the genetic 40 network underlying cancer can produce vulnerabilities to cytotoxic chemotherapy that 41 further influence the therapeutic window and provide additional insight into their 42 mechanisms of action [3,4]. A potential advantage of so-called synthetic lethality-based 43 treatment strategies is that they could have efficacy against passenger gene mutation or 44 compensatory gene expression, while classic targeted therapies are directed primarily at 45 driver genes ( Fig. 1A). Quantitative high throughput cell array phenotyping of the yeast 46 knockout and knockdown libraries provides a phenomic means for systems level, high- 47resolution modeling of gene interaction [5][6][7][8][9], which is applied here to predict cancer-48 relevant drug-gene interaction through integration with cancer pharmacogenomics 49 resources ( Fig. 1B). 50Nucleoside analogs include a diverse group of co...

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CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1

Cited by 51 publications

References 45 publications

Sirt1 Protects Cartilage Against Degradation through FoxO1 Nucleo-cytoplasmic Shuttling and Positive Regulation of Autophagy

Sirt1 Protects Cartilage Against Degradation through FoxO1 Nucleo-cytoplasmic Shuttling and Positive Regulation of Autophagy

Resveratrol protects against cadmium chloride‐induced hippocampal neurotoxicity by inhibiting ER stress and GAAD 153 and activating sirtuin 1/AMPK/Akt

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

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