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丝裂原和应激激活蛋白激酶1（MSK1）在癌基因诱导的衰老过程中触发INK4A/ARF基因座的表达。

MSK1 triggers the expression of the INK4AB/ARF locus in oncogene-induced senescence.

作者信息

Culerrier Raphaël, Carraz Maëlle, Mann Carl, Djabali Malek

机构信息

Université de Toulouse, UPS, LBCMCP, CNRS, F-31062 Toulouse, France.

Université de Toulouse, UPS, LBCMCP, CNRS, F-31062 Toulouse, France Institut de Recherche pour le Développement, IRD, UMR 152 Pharma-DEV, Faculté des Sciences Pharmaceutiques, Université Toulouse 3, F-31062 Toulouse, France.

出版信息

Mol Biol Cell. 2016 Sep 1;27(17):2726-34. doi: 10.1091/mbc.E15-11-0772. Epub 2016 Jul 6.

DOI:10.1091/mbc.E15-11-0772
PMID:27385346
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5007092/
Abstract

The tumor suppressor proteins p15(INK4B), p16(INK4A), and p14(ARF), encoded by the INK4AB/ARF locus, are crucial regulators of cellular senescence. The locus is epigenetically silenced by the repressive Polycomb complexes in growing cells but is activated in response to oncogenic stress. Here we show that the mitogen- and stress-activated kinase (MSK1) is up-regulated after RAF1 oncogenic stress and that the phosphorylated (activated) form of MSK1 is significantly increased in the nucleus and recruited to the INK4AB/ARF locus. We show that MSK1 mediates histone H3S28 phosphorylation at the INK4AB/ARF locus and contributes to the rapid transcriptional activation of p15(INK4B) and p16(INK4A) in human cells despite the presence of the repressive H3K27me3 mark. Furthermore, we show that upon MSK1 depletion in oncogenic RAF1-expressing cells, H3S28ph presence at the INK4 locus and p15(INK4B) and p16(INK4A) expression are reduced. Finally, we show that H3S28-MSK-dependent phosphorylation functions in response to RAF1 signaling and that ERK and p38α contribute to MSK1 activation in oncogene-induced senescence.

摘要

由INK4AB/ARF基因座编码的肿瘤抑制蛋白p15(INK4B)、p16(INK4A)和p14(ARF)是细胞衰老的关键调节因子。在生长的细胞中，该基因座被抑制性的多梳复合物表观遗传沉默，但在致癌应激反应中被激活。在此，我们表明，在RAF1致癌应激后，丝裂原和应激激活激酶(MSK1)上调，并且MSK1的磷酸化(激活)形式在细胞核中显著增加，并被招募到INK4AB/ARF基因座。我们表明，MSK1介导INK4AB/ARF基因座处组蛋白H3S28的磷酸化，并且尽管存在抑制性的H3K27me3标记，但仍有助于人细胞中p15(INK4B)和p16(INK4A)的快速转录激活。此外，我们表明，在表达致癌RAF1的细胞中耗尽MSK1后，INK4基因座处的H3S28ph存在以及p15(INK4B)和p16(INK4A)表达降低。最后，我们表明，H3S28-MSK依赖性磷酸化在响应RAF1信号时起作用，并且ERK和p38α在致癌基因诱导的衰老中有助于MSK1激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/c9835345db9d/2726fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/fddf63098c60/2726fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/9640bc645e8a/2726fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/b094a8329ea9/2726fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/054c786b90fe/2726fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/241a624398de/2726fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/c9835345db9d/2726fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/fddf63098c60/2726fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/9640bc645e8a/2726fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/b094a8329ea9/2726fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/054c786b90fe/2726fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/241a624398de/2726fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a437/5007092/c9835345db9d/2726fig6.jpg

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