Agmatine Mediated Arrest of Proliferation

描述(由申请人提供) 多胺(PA)是进入和前进所需的小阳离子分子。 通过细胞周期。为了满足他们对PA日益增长的需求，具有 短的循环时间上调PA的生物合成和PA的运输。帕 当细胞内高浓度PA诱导全长 活性蛋白，抗酶(Az)，通过翻译+1移码。AZ抑制 鸟氨酸是PA生物合成的第一酶和限速酶 脱羧酶(ODC)和PA转运。这两种机制有效地结合在一起 限制细胞获取PA的能力。 肾脏在显示高的细胞内苷胺(Agm)方面是例外的。 水平(-400微米)和高组成活性的转换 精氨酸转化为AGM、精氨酸脱羧酶(ADC)。肾脏似乎是一种重要的 系统性年度股东大会的来源。我们最近发现，AGM可以诱导Az。年度股东大会 Az的诱导耗尽转化细胞系的细胞内PA水平和 显著抑制它们的增殖。AGM是唯一已知的分子， 不包括标准PA，具有诱导Az的能力。 肾脏来源的抗增殖分子的进一步研究是 这是正当的。这一提议表明，AGM的摄取是通过PA转运蛋白实现的。这些 在静止的细胞中检测不到转运蛋白，并迅速上调 正在增殖的细胞。我们假设AGM有选择性地迅速锁定目标 正在增殖的细胞。在SA#1中，我们描述了AGM转运及其依赖性 在PA传送器上。在SA#2中，我们通过相对摄取量与 AGM在代表肿瘤发生发展阶段的细胞系中的作用。 在SA#3中，我们讨论了AGM介导的抑制增殖的机制。 我们推测，这种活跃的细胞介导机制可能类似于 以衰老著称。 获得K01奖将使PI正式确立他的独立性 对于未来的R01申请，并寻求学术上的任命 加州大学圣地亚哥分校的研究系列。加州大学圣迭戈分校已建立 作为领先的学术机构，因此提供了一个优秀的 交流思想和技术的环境对企业的发展至关重要 私家侦探的职业生涯。

DESCRIPTION (provided by applicant) Polyamines (PA) are small cationic molecules required for entry and progression through the cell cycle. To address their increased need for PA, cells with short cycling times up-regulate both PA biosynthesis and PA transport. PA autoregulate when high intracellular PA concentrations induce a full-length active protein, antizyme (Az), via a translational +1 frameshift. Az inhibits both the first and rate-limiting enzyme of PA biosynthesis, ornithine decarboxylase (ODC), and PA transport. This 2 pronged mechanism effectively limits the ability of the cell to acquire PA. The kidney is exceptional in demonstrating high intracellular agmatine (Agm) levels (-400 uM) and high constitutive activity of the enzyme that converts arginine to Agm, arginine decarboxylase (ADC). The kidney appears an important source of systemic Agm. We have recently shown that Agm can induce Az. Agm induction of Az depletes intracellular PA levels in transformed cell lines and markedly inhibits their proliferation. Agm is the only known molecule, exclusive of the canonical PA, with the capacity to induce Az. Further investigation of this kidney derived anti-proliferative molecule is warranted. This proposal demonstrates Agm uptake is via PA transporters. These transporters are undetectable in quiescent cells, and up regulated in rapidly proliferating cells. We hypothesize that Agm selectively targets rapidly proliferating cells. In SA #1 we characterize Agm transport and its dependence on PA transporters. In SA#2 we evaluate targeting via the relative uptake vs. effects of Agm in cell lines representing increasing stages of tumorigenesis. In SA #3 we address the mechanisms of Agm mediated inhibition of proliferation. We hypothesize that this active cell mediated mechanism may be analogous to that noted for senescence. Attaining a K01 award would allow the PI to formally establish his independence for future R01 applications, and to pursue an appointment in the Academic Research series at the University of California San Diego. UCSD has established itself as a leading academic institution and thus provides an excellent environment for the exchange of ideas and techniques essential for the growth of the PI's career.