Agmatine Mediated Arrest of Proliferation

描述（由申请人提供） 多胺（PA）是进入和进展所需的小阳离子分子 通过细胞周期。为了解决他们对PA的需求增加， 短循环时间上调PA生物合成和PA转运。PA 当高细胞内PA浓度诱导全长PA时， 活性蛋白，抗酶（Az），通过翻译+1移码。AZ抑制 作为PA生物合成的第一个和限速酶， 脱羧酶（ODC）和PA转运。这两个机制有效地 限制了细胞获得PA的能力。 肾脏是一个例外，表现出高细胞内胍丁胺（Agm） 水平（~ 400 μ M）和高组成型活性的酶， 精氨酸转化为Agm，精氨酸脱羧酶（ADC）。肾脏似乎是一个重要的 系统性Agm的来源。我们最近发现，Agm可以诱导Az。周年大会 Az的诱导消耗转化细胞系中的细胞内PA水平， 明显抑制其增殖。Agm是唯一已知的分子， 不包括典型的PA，具有诱导Az的能力。 对这种肾源性抗增殖分子的进一步研究 有正当理由该提议表明Agm摄取是通过PA转运蛋白。这些 转运蛋白在静止期细胞中检测不到，并且在细胞中快速上调。 增殖细胞。我们假设Agm选择性快速靶向 增殖细胞在SA #1中，我们描述了Agm输运及其依赖性 在PA传输器上在SA#2中，我们通过相对摄取与 Agm在代表肿瘤发生阶段增加的细胞系中的作用。 在SA #3中，我们解决了Agm介导的增殖抑制的机制。 我们假设这种活性细胞介导的机制可能类似于 以衰老而著称。 获得K 01奖项将使PI正式确立其独立性 为未来的R 01应用程序，并追求在学术任命 加州圣地亚哥大学的研究系列。UCSD建立了 作为一个领先的学术机构本身，从而提供了一个优秀的 环境的思想和技术交流的增长至关重要 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.