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Series GSE210949 Query DataSets for GSE210949
Status Public on Jun 09, 2023
Title ERK5 S496 phosphorylation, but not ERK5 kinase activation, promotes senescence-associated cell growth (SACG) and inflammation of myeloid cells and atherosclerosis via upregulating SUMOylation at a novel site (K518) on NRF2 and aryl hydrocarbon receptor
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary ERK5 is a dual kinase-transcription factor, which contains an N-terminal kinase domain and transactivation domains in the C-terminal half. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions regarding the functional role of ERK5 kinase inhibitors. We aimed to investigate how ERK5 reprograms myeloid cells (MC) to the senescence-associated secretory phenotype (SASP), consequently leading to atherosclerosis. We showed that atherosclerosis was inhibited in ERK5 S496A (dephosphorylation mimic) knock-in (KI) mice. Furthermore, ERK5 S496 phosphorylation was required for not only SASP but also senescence-associated cell growth (SACG) observed in the plaque via upregulation of aryl hydrocarbon receptor (AHR). We also discovered a key effect of ERK5 S496 phosphorylation on SUMOylation at a novel site of NRF2 (i.e., K518), which inhibited NRF2 transcriptional activity without affecting ERK5 kinase activity and antagonized oxidized LDL (oxLDL)-induced SASP. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) both inhibited oxLDL-induced ERK5 S496 phosphorylation, suggesting that ERK5 S496 phosphorylation was involved at least in part of the effects of these inhibitors. We have discovered a novel mechanism, in which ERK5 S496 phosphorylation directly inhibits NRF2 activity by upregulating NRF2 K518 SUMOylation, and induces SACG and atherosclerosis.
Overall design We prepared the tissue section from the plaques in wild-type, and ERK5 S496A KI mice fed a high-fat diet (HFD) or normal chow diet (NCD) for 12 weeks after AAV8-PCSK9 injection.
Contributor(s) Abe J, Imanishi M, Li S, Zhang A, Ko KA, Samanthapudi VK, Lee L, Deswal A, Herrmann J, Lin SH, Chini EN, Shen YH, Schadler KL, Nguyen T, Gupte AA, Reyes-Gibby C, Yeung SJ, Palaska NL, Cooke JP, Pownall HJ, Yoshimoto M, Fujiwara K, Hamilton DJ, Burks JK, Wang G, Le N, Kotla S
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Submission date Aug 10, 2022
Last update date Jun 09, 2023
Contact name Shengyu Li
Phone 3462386130
Organization name Houston Methodist Research Insitute
Street address 6670 Bertner Ave, R10-109, floor 10
City Houston
State/province TX
ZIP/Postal code 77030
Country USA
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (12)
GSM6443240 BMDMs, WT, NCD_1
GSM6443241 BMDMs, WT, HFD_1
GSM6443242 BMDMs, ERK5S496A, NCD_1
BioProject PRJNA868360

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Supplementary file Size Download File type/resource
GSE210949_FPKM_samples.csv.gz 680.7 Kb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record

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