Percy Melanie J, Zhao Quan, Flores Adrian, Harrison Claire, Lappin Terence R J, Maxwell Patrick H, McMullin Mary Frances, Lee Frank S
Department of Haematology, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland, United Kingdom.
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9. doi: 10.1073/pnas.0508423103. Epub 2006 Jan 9.
The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigations of erythropoietin regulation identified the transcription factor hypoxia-inducible factor (HIF). HIF is now recognized as being a key regulator of genes that function in a comprehensive range of processes besides erythropoiesis, including energy metabolism and angiogenesis. HIF itself is regulated through the alpha-subunit, which is hydroxylated in the presence of oxygen by a family of three prolyl hydroxylase domain proteins (PHDs)/HIF prolyl hydroxylases/egg-laying-defective nine enzymes. Hydroxylation allows capture by the von Hippel-Lindau tumor suppressor gene product, ubiquitination, and destruction by the proteasome. Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a previously unrecognized cause of this condition. Our findings indicate that PHD2 is critical for normal regulation of HIF in humans.
红细胞数量通常通过基于肾脏中氧感应的经典稳态机制受到严格调控。贫血导致的氧输送减少会诱导促红细胞生成素的产生，促红细胞生成素会增加红细胞生成，从而增加氧输送。对促红细胞生成素调控的研究确定了转录因子缺氧诱导因子（HIF）。现在人们认识到，HIF是除红细胞生成外，在包括能量代谢和血管生成在内的一系列广泛过程中发挥作用的基因的关键调节因子。HIF自身通过α亚基进行调节，在有氧存在的情况下，α亚基会被一个由三种脯氨酰羟化酶结构域蛋白（PHD）/HIF脯氨酰羟化酶/产卵缺陷9酶组成的家族羟基化。羟基化使得它能被冯·希佩尔-林道肿瘤抑制基因产物捕获，进行泛素化，并被蛋白酶体降解。在此，我们描述了一种哺乳动物PHD酶中的遗传性突变。我们表明，PHD2中的这种突变导致酶活性显著降低，并与家族性红细胞增多症相关，从而确定了这种病症一个此前未被认识到的病因。我们的研究结果表明，PHD2对人类HIF的正常调节至关重要。
