MEN1 Missense Mutations Impair Sensitization to Apoptosis Induced by Wild-Type Menin in Endocrine Pancreatic Tumor Cells
MEN1 Missense Mutations Impair Sensitization to Apoptosis Induced by Wild-Type Menin in Endocrine Pancreatic Tumor Cells
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DOI：
10.1053/j.gastro.2008.07.031
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发表时间：
2008-11-01
期刊：
影响因子：
29.4
通讯作者：
Cordier-Bussat, Martine
中科院分区：
文献类型：
--
作者：
Bazzi, Wissam;Renon, Maud;Cordier-Bussat, Martine
背景和目标：错义突变占多发性内分泌瘤1型（MEN 1）综合征患者中确定的突变的30%。它们提出了几个问题：致病性突变和多态性之间的区别有时是困难的，并且错义突变的功能影响也不清楚。我们的目的是评估MEN 1错义突变在适当的内分泌细胞环境中的功能后果。研究方法：从INS-1胰岛素瘤细胞系中，我们建立了条件性过表达野生型（WT）menin或其A160 T、H317 Y和AS 41 T变体的克隆。我们比较了WT或变异menin过表达对γ射线照射后凋亡反应的影响，并分析了这些蛋白与p53的相互作用。结果如下：WT menin的过度表达敏感的INS-r3细胞凋亡，通过放大半胱天冬酶-3激活，增加p53乙酰化，并加速p21激活;此外，过度表达的WT menin可以恢复在含p53的复合物。对于测试的所有3种错义突变，用WT观察到的功能效应显著受损，并且在含有p53的复合物中仅回收少量的变体menin蛋白。结论：利用一种新的内分泌细胞模型，我们发现2个错义疾病相关的menin突变体和一个有争议的变体功能丧失。此外，我们的研究结果表明，p53和menin之间存在的功能相互作用的控制细胞凋亡，这可能会投下新的光的内分泌肿瘤的发生机制。
Background & Aims: Missense mutations account for 30% of mutations identified in patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome. They raise several issues: the distinction between pathogenic mutations and polymorphisms is sometimes difficult and the functional effects of missense mutations are unclear. We aimed to evaluate the functional consequences of missense MEN1 mutations in an appropriate endocrine cellular context. Methods: From the INS-1 insulinoma cell line, we established clones conditionally over expressing wildtype (WT) menin or its A160T, H317Y, and AS41T variants. We compared the consequences of WT or variant menin over expression on apoptotic response after gamma-irradiation and analyzed the interactions of these proteins with p53. Results: WT menin over expression sensitized INS-r3 cells to apoptosis through amplification of caspase-3 activation, increased p53 acetylation, and accelerated p21 activation; moreover, over expressed WT menin could be recovered in p53-containing complexes. For all 3 missense mutations tested, the functional effects observed with WT were impaired significantly and only low amounts of variant menin proteins were recovered in p53-containing complexes. Conclusions: Taking advantage of a new endocrine cellular model, we show a loss of function for 2 missense disease-related menin mutants and for a controversial variant as well. Furthermore, our results suggest the existence of functional interactions between p53 and menin for the control of apoptosis, which may cast new light on the mechanisms of endocrine tumorigenesis.