Shen Chuan, Powell-Coffman Jo Anne
Department of Zoology and Genetics, Iowa State University, Iowa 50010-3260, USA.
Ann N Y Acad Sci. 2003 May;995:191-9. doi: 10.1111/j.1749-6632.2003.tb03222.x.
During normal development and homeostasis, animals use cellular and systemic strategies to adapt to changing oxygen levels. In mammals, hypoxic tissues secrete growth factors to induce angiogenesis, and individual cells increase anaerobic metabolism in order to sustain basic cellular functions. Many of these critical responses to decreased oxygen availability are regulated by the hypoxia-inducible factors, dimeric transcriptional complexes consisting of alpha and beta subunits. HIFalpha proteins are specialized for hypoxia response, and oxygen levels regulate their stability and activity. The C. elegans hif-1 gene is orthologous to mammalian HIFalpha genes, and C. elegans has proven to be a powerful system for the study of hypoxia-inducible factor regulation and function. Mutants lacking hif-1 function are viable in normoxic or anoxic conditions, but they cannot adapt to hypoxia. Recent genetic analyses in C. elegans led to the identification of the evolutionarily conserved enzyme that hydroxylates HIFa in an oxygen-dependent manner. Once modified, HIFalpha binds the von Hippel-Lindau tumor suppressor protein and is targeted for proteasomal degradation. Here, we briefly review the characterization of C. elegans hif-1 and interacting genes, and discuss genetic strategies for studying hypoxia signaling and response.
在正常发育和体内平衡过程中，动物会利用细胞和全身策略来适应不断变化的氧水平。在哺乳动物中，缺氧组织会分泌生长因子以诱导血管生成，单个细胞会增加无氧代谢以维持基本的细胞功能。许多对氧供应减少的关键反应是由缺氧诱导因子调节的，缺氧诱导因子是由α和β亚基组成的二聚体转录复合物。HIFα蛋白专门用于缺氧反应，氧水平调节其稳定性和活性。秀丽隐杆线虫的hif-1基因与哺乳动物的HIFα基因是直系同源的，秀丽隐杆线虫已被证明是研究缺氧诱导因子调节和功能的强大系统。缺乏hif-1功能的突变体在常氧或缺氧条件下都能存活，但它们无法适应缺氧环境。最近在秀丽隐杆线虫中的遗传分析导致鉴定出一种以氧依赖方式使HIFα羟基化的进化保守酶。一旦被修饰，HIFα就会与冯·希佩尔-林道肿瘤抑制蛋白结合，并被靶向蛋白酶体降解。在这里，我们简要回顾秀丽隐杆线虫hif-1及其相互作用基因的特征，并讨论研究缺氧信号传导和反应的遗传策略。
