External factors
| External factors: |
Pevonedistat |
| Category: |
Chemical compounds |
| Experimental category: |
HL |
| Experiment: |
SA-β-gal activity assay//Western blot//Flow cytometry |
| Description: |
Cells treated with pevonedistat for 12 or 24 h remained arrested, and exhibited 18% and 60% rereplication, respectively when analyzed 48 h later and were senescent. Furthermore,treatment of DM93 cells with vemurafenib induced robust G1 growth arrest and complete depletion of S-phase cells, and inhibited pevonedistat-induced rereplication . |
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Regulatory relationship
| Regulatory pathway:
|
CRL4-CDT2-SET8-p21 |
| Official symbol(s): |
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CRL4-CDT2-SET8-CDKN1A
|
| Pathway experiment: |
Western blot//Clonogenic assay |
| Pathway description: |
We treated DM93 cells with increasing doses of pevonedistat for 24 h. This resulted in a dose-dependent increase in several cullin ubiquitylation substrates, including CDT2, CDT1, p21 and p27,which reached significant levels at 1 μM drug concentration. Although CDT2 is increased by pevonedistat,it is likely to be inActivate because of the de-neddylation of cullin proteins.Time course analysis with 1 μM pevonedistat demonstrated early (at 3 and 6 h) increase in CDT1 as well as SET8 protein and activity (H4K20 monomethylation) followed by th appearance of p21 and p27 .Increases in CDT1, SET8 and p21 were all attributed to increased stability as well as increase in the stability of not only H4K20me1, but also H4K20me2 and H4K20me3. When added continuously in culture, pevonedistat still inhibited the proliferation of sg-p21 and sg-SET8 cells.Strikingly however,unlike control cells (sg-control), cells with reduced expression of p21 or SET8 resumed proliferation following the cessation of pevonedistat treatment . Thus, pevonedistat inhibits the proliferation of melanoma cells through the induction of SET8- and p21-dependent rereplication mechanism. |
Aging network
Annotation:
The green line represents Upregulation.
The purple line represents Downregulation.
The orange line represents Activation.
The yellow line represents Inhibition.
The gray line represents Unclear.
Pathway view
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