Molecular control of iron-sensing in yeast.

标题。酵母铁敏感的分子调控。所有真核生物都需要铁(Fe)才能生存。这种过渡金属以两种氧化还原状态存在，这使得它在许多酶和电子转运体的活性中心都是必不可少的。矛盾的是，使铁在这些反应中必不可少的性质在某些条件下也会使其有毒。过量的铁能够释放有毒的氧自由基，从而破坏细胞成分。因此，生物体必须严格调节体内的铁负荷，并通过控制铁的获取和区划来做出适当的反应，以维持体内的动态平衡。酵母裂殖酵母是了解真核细胞生长、代谢和信号转导许多方面的优秀模型系统。对S.pombe的研究已经发现了调节铁运输的新基因，并揭示了它们在其他生物体中的存在和重要性。作为对高铁的反应，Fep1转录因子抑制了一系列与铁的获得有关的基因的表达。在铁限制条件下，细胞铁利用的优化是由Php4蛋白协调的，Php4蛋白作为CCAAT结合因子的负调控亚单位，促进对编码铁利用蛋白的基因的抑制。尽管最近有这些发现，但人们对Fep1和Php4对低或高铁利用率的反应机制知之甚少。此外，我们对许多Fep1/Php4靶基因(&gt；40个未开发基因)的产物的功能作用知之甚少。总体而言，这项拟议的研究将提供对依赖铁的细胞过程的分子电路的更好理解，包括Fep1和Php4对铁的感知，以及依赖液泡铁转运蛋白ABC3的铁运输。该计划的长期目标是利用这些知识更好地理解铁稳态的分子基础，并利用结果与其他生命系统进行比较。拟议的工作还为培训高素质的人员提供了一个难得的机会，使他们对加拿大生物技术部门和/或学术研究界具有极高的价值。

Title. Molecular control of iron-sensing in yeast. All eukaryotes require iron (Fe) for survival. The ability of this transition metal to exist in two redox states makes it essential at the active center of many enzymes and electron transporters. Paradoxically, the properties that make Fe essential in these reactions can also make it toxic under certain conditions. Excess Fe has the ability to unleash toxic oxygen radicals that can damage cellular components. Consequently, organisms must tightly regulate their internal Fe load, and respond appropriately by controlling Fe acquisition and compartmentalization to maintain homeostasis. The yeast Schizosaccharomyces pombe is an outstanding model system for understanding many aspects of eukaryotic cell growth, metabolism, and signal transduction. Studies of S. pombe have identified novel genes that function in the regulation of Fe transport and have revealed their existence and importance in other organisms. In response to high Fe, the Fep1 transcription factor represses the expression of a set of genes involved in the acquisition of Fe. Under Fe-limiting conditions, optimization of cellular Fe utilization is coordinated by the Php4 protein, which acts as a negative regulatory subunit of the CCAAT-binding factor and fosters repression of genes encoding Fe-using proteins. Despite these recent findings, little is known about the mechanisms by which Fep1 and Php4 respond to low or high Fe availability. Furthermore, we know little about the functional roles of the products of many Fep1/Php4 target genes (>40 unexplored genes). Overall, the proposed research will provide a better understanding of the molecular circuitry of Fe-dependent cellular processes, including Fe-sensing by Fep1 and Php4, and Fe-trafficking that relies on the vacuolar Fe transporter Abc3. The long-term objective of this program is to use this knowledge to better understand the molecular basis of Fe homeostasis and use the results to draw parallels with other living systems. The proposed work also promises an exceptional opportunity for the training of highly qualified personnel, making them highly valuable to the Canadian biotech sector and/or academic research community.