Regulation of apoptosis by menin

-描述（申请人提供）：I型多发性内分泌瘤（MEN1）是一种以多内分泌器官肿瘤发展为特征的显性遗传肿瘤综合征，偶尔发生在非内分泌器官。MEN1患者体内发生突变的基因MEN1编码一种含有610个氨基酸残基的蛋白质menin。在小鼠中，Men1的靶向破坏也会导致内分泌肿瘤综合征，与人类Men1非常相似，这表明menin具有真正的肿瘤抑制功能。由于在menin中没有明显的提示任何生化功能的结构域，阐明menin在肿瘤抑制中的关键作用的机制是一项具有挑战性但又令人兴奋的工作。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。我们发现脑膜蛋白对于最佳的tnf α诱导的细胞凋亡至关重要。此外，menin直接结合DNA，两个MEN1疾病相关突变体不能结合DNA。此外，menin在caspase 8的转录中起着至关重要的作用，并结合内源性caspase 8的启动子，而两个men1相关的menin点突变体未能激活caspase 8的表达和tnf -a诱导的细胞凋亡。其他最近的报道表明menin与组蛋白甲基转移酶相关，通常会激活基因转录。综上所述，这些结果使我们推测menin与DNA结合并将其他转录调节因子招募到caspase 8基因的启动子上，从而导致MEN1中caspase 8转录上调和tnf α诱导的细胞凋亡，并抑制肿瘤发生。

-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.