The menin tumor suppressor protein is phosphorylated in response to DNA damage.
The menin tumor suppressor protein is phosphorylated in response to DNA damage.
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DOI：
10.1371/journal.pone.0016119
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发表时间：
2011-01-14
期刊：
影响因子：
3.7
通讯作者：
Meyerson M
中科院分区：
文献类型：
--
作者：
Francis J;Lin W;Rozenblatt-Rosen O;Meyerson M
多发性内分泌瘤1型（MEN1）是一种遗传性癌症综合征，以垂体、胰腺和甲状旁腺肿瘤为特征。Menin是MEN1基因的产物，是一种肿瘤抑制蛋白，其部分功能是通过与染色质修饰酶相互作用介导的转录调节。我们发现，menin与DNA损伤后DNA损伤反应基因5′端区域的相关性增加，并与RNA聚合酶II相关，但与组蛋白甲基化的变化无关。此外，我们能够在DNA损伤后转录增强的条件下，在CDKN 1A和GADD 45 A的3′区域检测到显著水平的menin。我们还表明，menin是专门磷酸化Ser394在几种形式的DNA损伤，Ser487是动态磷酸化和Ser543组成性磷酸化。然而，这些位点的磷酸化并不影响与组蛋白甲基转移酶活性相互作用的能力。相比之下，menin和RNA聚合酶II之间的相互作用受到磷酸化的影响，由此磷酸缺陷突变体与野生型相比对RNA聚合酶的延伸形式具有更高的亲和力。此外，MEN1相关的错义点突变体的一个子集不能经历DNA损伤依赖性磷酸化。总之，我们的研究结果表明，menin肿瘤抑制蛋白经历DNA损伤诱导的磷酸化，并参与DNA损伤转录反应。
Multiple endocrine neoplasia type 1 (MEN1) is a heritable cancer syndrome characterized by tumors of the pituitary, pancreas and parathyroid. Menin, the product of the MEN1 gene, is a tumor suppressor protein that functions in part through the regulation of transcription mediated by interactions with chromatin modifying enzymes. Here we show menin association with the 5′ regions of DNA damage response genes increases after DNA damage and is correlated with RNA polymerase II association but not with changes in histone methylation. Furthermore, we were able to detect significant levels of menin at the 3′ regions of CDKN1A and GADD45A under conditions of enhanced transcription following DNA damage. We also demonstrate that menin is specifically phosphorylated at Ser394 in response to several forms of DNA damage, Ser487 is dynamically phosphorylated and Ser543 is constitutively phosphorylated. Phosphorylation at these sites however does not influence the ability to interact with histone methyltransferase activity. In contrast, the interaction between menin and RNA polymerase II is influenced by phosphorylation, whereby a phospho-deficient mutant had a higher affinity for the elongating form of RNA polymerase compared to wild type. Additionally, a subset of MEN1-associated missense point mutants, fail to undergo DNA damage dependent phosphorylation. Together, our findings suggest that the menin tumor suppressor protein undergoes DNA damage induced phosphorylation and participates in the DNA damage transcriptional response.
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影响因子：
16
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
Hughes, CM;Rozenblatt-Rosen, O;Meyerson, M
通讯作者：
Meyerson, M
DOI：
10.1196/annals.1294.020
发表时间：
2004-01-01
期刊：
GASTROENTEROPANCREATIC NEUROENDOCRINE TUMOR DISEASE: MOLECULAR AND CELL BIOLOGICAL ASPECTS
影响因子：
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作者：
Agarwal, SK;Burns, L;Marx, SJ
通讯作者：
Marx, SJ