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. 2022 Sep 19;79(10):524. doi: 10.1007/s00018-022-04541-6

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — ERK5 inhibition impairs EC cell proliferation. A Genomic profiles of components of the MEK5-ERK5 pathway in EC patients obtained from Uterine Corpus Endometrial Carcinoma data set (TCGA, PanCancer Atlas). Data set from cBiportal (https://www.cbioportal.org/). MAPK7, ERK5 gene; MAP2K5, MEK5. B Kaplan–Meier plots overall survival (left) and progression-free (right) in uterine corpus endometrial carcinoma patients with high (red), quartile 1) or normal (blue, quartile 2–3) ERK5 mRNA levels (data set from cBioportal). P values were obtained using log-rank test. C Chemical structure of JWG-071. D Immunoblot analysis of the effect of JWG-071 on EGF stimulation. E MTT cytotoxicity (48 h) assay in a panel of human EC cells. F 14-day clonogenic assay. G Effect of ERK5 silencing on the proliferation of EC cell. ERK5 silencing was carried out with two different specific siRNA sequences. Scr., scramble siRNA. Cell proliferation was measured at three days of culture using crystal violet assays. ^***, P < 0.001. H LRRK2 or DCLK1 inhibition does not affect human EC cell proliferation. Ishikawa or AN3CA cells were incubated for 48 h with either the specific DCLK1 inhibitor DCLK1-IN-1 or the LRRK2 specific inhibitor MLi-2, and cell proliferation was assessed by crystal violet assay. I Effect of ERK5 inhibitors JWG-071 and AX15836 in EGF-induced cell proliferation. Histograms show number of cells at day 4 referred to cells at day 0. ^$, P < 0.05; ^$$$, P < 0.001 EGF vs. vehicle. **, P < 0.01; ***, P < 0.001 ERK5i vs. EGF. J, JWG-071 blocks EGF-induced ERK5 nuclear localization. HeLa cells were pre-incubated with 3 µM JWG-071 prior stimulation with 50 nM EGF (30 min), fractionated into the cytosolic and nuclear fractions, and protein expression analyzed by immunoblot. Hsp90, cytosolic marker; CREB-1, nuclear marker. K ERK5 inhibition impairs EGF-induced c-Jun expression in Ishikawa cells. Immunoblot analysis. L JWG-071 impairs ERK5-mediated AP-1 transcriptional activity. Hela cells transfected with vectors encoding pAP-1–luciferase reporter and pRL-CMV-Renilla were subjected to a dual-luciferase reporter assay. **, P < 0.005