Regulation of apoptosis by menin

多发性内分泌瘤I型（MEN 1）是一种显性遗传性肿瘤综合征 特征为在多个内分泌器官和偶尔在非内分泌器官中发生肿瘤 机关在MEN 1患者中突变的基因Menl编码610个氨基酸残基的蛋白质menin。 小鼠中Menl的靶向破坏也导致内分泌肿瘤综合征，其与肿瘤的发生密切相关。 人MEN 1，提示menin具有真正的肿瘤抑制功能。由于没有明显的 结构域的menin，建议任何生化功能，它一直是具有挑战性的，但令人兴奋的阐明 the mechanisms机制underlying潜在the critical关键role作用of menin脑膜瘤in tumor肿瘤suppression抑制.最近，我们 在理解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。我们证明了 menin对于最佳TNF-α诱导的细胞凋亡是必需的。此外，menin直接结合DNA，两个 MEN 1疾病相关突变体不能结合DNA。此外，menin在半胱天冬酶8中起重要作用 转录并且还结合内源性胱天蛋白酶8的启动子，而两个MEN 1相关的脑膜炎相关蛋白酶 突变体不能激活Casapse 8表达和TNF-α诱导的细胞凋亡。最近的其他报告显示， menin与通常激活基因转录的组蛋白甲基转移酶相关。所有这些 结果使我们假设menin与DNA结合，并招募其他转录调节因子， caspase 8基因的启动子，导致caspase 8转录的上调和TNF-α诱导的凋亡。 细胞凋亡以及抑制MENL中的肿瘤发生 提出了三个具体目标来检验这些假设。首先，我们将确定最小值 menin的DNA结合结构域及其与DNA相互作用在caspase 8调控中的作用 表达和TNF-α诱导的凋亡。其次，我们将研究menin，组蛋白 甲基转移酶和其他脑膜炎相互作用蛋白在半胱天冬酶8的转录调节和 第三，menin介导的caspase 8表达在抑制TNF-α诱导的细胞凋亡中的作用。 将在经典和条件性Men 1敲除小鼠中评价Men 1肿瘤发生。从这些 独立但互补的研究可能会大大促进我们对分子的理解 MEN 1发展的电路，并阐明了MEN 1和MEN 2的治疗干预措施， 其他相关肿瘤

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, Menl, encodes a protein of 610 amino acid residues, menin. Targeted disruption of Menl in mice also leads to an endocrine tumor syndrome that closely mimics the human MEN1, indicatinga bonafide 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 underlyingthe crucial role of menin in tumor suppression. Recently, we have made significant progress in understanding a vital role for menin in TNF-a-mediated apoptosis. We show that menin is essential for optimal TNF-a-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 MENl-related meninpoint mutants fail to activate casapse 8 expression and TNF-a-induced apoptosis. Other recent reports show that menin associates with histone methyltransferases that usuallyactivates gene transcription. Together, these results lead us to hypothesize that menin binds to DNAand recruits other transcriptional regulators to the promoter of the caspase 8 gene, resulting in upregulation of caspase 8 transcription and TNF-a-induced apoptosis, as well as suppression of tumorigenesis in MENL 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-a-induced apoptosis. Second, we will examine the role of menin, histone methyltransferases and other menin-interactingproteins in the transcriptional regulation of caspase 8 and TNF-a-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 understandingof the molecular circuitry of the MEN1 development and shed lights on improvingtherapeutic interventionsfor MEN1 and other related tumors.