Jobst, Belinda and Weigl, Julia and Michl, Carina and Vivarelli, Fabio and Pinz, Sophia and Amslinger, Sabine and Rascle, Anne (2016) Inhibition of interleukin-3-andinterferon-alpha-induced JAK/STAT signaling by the synthetic alpha-X-2 ',3,4,4 '-tetramethoxychalcones alpha-Br-TMC and alpha-CF3-TMC. BIOLOGICAL CHEMISTRY, 397 (11). pp. 1187-1204. ISSN 1431-6730, 1437-4315
Full text not available from this repository. (Request a copy)Abstract
The JAK/STAT pathway is an essential mediator of cytokine signaling, often upregulated in human diseases and therefore recognized as a relevant therapeutic target. We previously identified the synthetic chalcone-alpha-bromo-2',3,4,4'-tetramethoxychalcone (alpha-Br-TMC) as a novel JAK2/STAT5 inhibitor. We also found that treatment with alpha-Br-TMC resulted in a downward shift of STAT5 proteins in SDS-PAGE, suggesting a post-translational modification that might affect STAT5 function. In the present study, we show that a single cysteine within STAT5 is responsible for the alpha-Br-TMC-induced protein shift, and that this modification does not alter STAT5 transcriptional activity. We also compared the inhibitory activity of alpha-Br-TMC to that of another synthetic - chalcone, alpha-trifluoromethyl-2',3,4,4'-tetramethoxychalcone (alpha-CF3-TMC). We found that, like alpha-Br-TMC, alpha-CF3-TMC inhibits JAK2 and STAT5 phosphorylation in response to interleukin-3, however without altering STAT5 mobility in SDS-PAGE. Moreover, we demonstrate that both alpha-Br-TMC and alpha-CF3-TMC inhibit interferon-alpha-induced activation of STAT1 and STAT2, by inhibiting their phosphorylation and the expression of downstream interferon-stimulated genes. Together with the previous finding that alpha-Br-TMC and alpha-CF3-TMC inhibit the response to inflammation by inducing Nrf2 and blocking NF-kappa B activities, our data suggest that synthetic chalcones might be useful as anti-inflammatory, anti-cancer and immunomodulatory agents in the treatment of human diseases.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; DEACETYLASE ACTIVITY; C-MYC; S-GLUTATHIONYLATION; CYTOKINE RESPONSES; MYELOID-LEUKEMIA; STAT5 ACTIVATION; INTERFERON-ALPHA; TARGET GENES; IN-VIVO; chalcone; cysteine; gene expression; mutagenesis; phosphorylation; STAT1/2/5 |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie Chemistry and Pharmacy > Institut für Organische Chemie > Arbeitskreis Dr. Sabine Amslinger |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Apr 2019 09:11 |
| Last Modified: | 24 Apr 2019 09:11 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4042 |
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