Regulation of apoptosis by menin

- 描述（由申请人提供）：多发性内分泌瘤形成I型（MEN 1）是一种显性遗传性肿瘤综合征，其特征在于肿瘤在多个内分泌器官中发展，偶尔在非内分泌器官中发展。 在MEN 1患者中突变的基因Men 1编码610个氨基酸残基的蛋白质menin。 在小鼠中靶向破坏Men 1也会导致内分泌肿瘤综合征，该综合征与人类MEN 1非常相似，表明menin具有真正的肿瘤抑制功能。 由于menin中没有明显的结构域表明任何生物化学功能，因此阐明menin在肿瘤抑制中的关键作用的机制一直是具有挑战性但令人兴奋的。 最近，我们在了解menin在TNF-α介导的细胞凋亡中的重要作用方面取得了重大进展。 我们发现menin对最佳TNF-α诱导的细胞凋亡是必不可少的。 此外，menin直接结合DNA，而两种MEN 1疾病相关突变体不能结合DNA。 此外，menin在半胱天冬酶8转录中起重要作用，并且还结合内源性半胱天冬酶8的启动子，而两个MEN 1相关的menin点突变体不能激活半胱天冬酶8表达和TNF-α诱导的细胞凋亡。 其他最近的报告表明，menin与组蛋白甲基转移酶，通常激活基因转录。 总之，这些结果使我们假设，menin结合到DNA和招募其他转录调节caspase 8基因的启动子，导致caspase 8转录上调和TNF-α诱导的细胞凋亡，以及抑制MEN 1的肿瘤发生。 提出了三个具体目标来检验这些假设。 首先，我们将确定最小的DNA结合结构域在menin和menin-DNA相互作用的作用，在调节caspase 8的表达和TNF-α诱导的细胞凋亡的特点。 其次，我们将研究menin，组蛋白甲基转移酶和其他menin相互作用蛋白在caspase 8和TNF-α诱导的细胞凋亡的转录调控中的作用。 第三，将在经典和条件性Men 1敲除小鼠中评估menin介导的半胱天冬酶8表达在抑制MEN 1肿瘤发生中的作用。 这些独立但互补的研究结果可能会显着促进我们对MEN 1发展的分子电路的理解，并为改善MEN 1和其他相关肿瘤的治疗干预提供线索。

-DESCRIPTION (provided by applicant): Multiple endocrine neoplasia type I (MEN1) is a dominantly inherited tumor syndrome characterized by development of tumors in multiple endocrine organs and occasionally in non-endocrine organs. The gene mutated in MEN1 patients, Men1, encodes a protein of 610 amino acid residues, menin. Targeted disruption of Men1 in mice also leads to an endocrine tumor syndrome that closely mimics the human MEN1, indicating a bona fide tumor suppressing function for menin. Since there are no obvious domains in menin that suggest any biochemical functions, it has been challenging yet exciting to elucidate the mechanisms underlying the crucial role of menin in tumor suppression. Recently, we have made significant progress in understanding a vital role for menin in TNF-alpha-mediated apoptosis. We show that menin is essential for optimal TNF-alpha-induced apoptosis. Moreover, menin directly binds DNA, and two MEN1 disease-related mutants fail to bind DNA. Furthermore, menin plays an essential role in caspase 8 transcription and also binds the promoter of endogenous caspase 8, while two MEN1-related menin point mutants fail to activate caspase 8 expression and TNF-a-induced apoptosis. Other recent reports show that menin associates with histone methyltransferases that usually activates gene transcription. Together, these results lead us to hypothesize that menin binds to DNA and recruits other transcriptional regulators to the promoter of the caspase 8 gene, resulting in upregulation of caspase 8 transcription and TNF-alpha-induced apoptosis, as well as suppression of tumorigenesis in MEN1. Three Specific Aims have been proposed to test these hypotheses. First, we will identify the minimal DNA binding domain in menin and characterize the role of menin-DNA interaction in regulating caspase 8 expression and TNF-alpha-induced apoptosis. Second, we will examine the role of menin, histone methyltransferases and other menin-interacting proteins in the transcriptional regulation of caspase 8 and TNF-alpha-induced apoptosis. Third, the role of menin-mediated expression of caspase 8 in suppressing the MEN1 tumorigenesis will be evaluated in classic and conditional Men 1 knock out mice. Results from these independent yet complementary studies will likely significantly advance our understanding of the molecular circuitry of the MEN1 development and shed lights on improving therapeutic interventions for MEN1 and other related tumors.