Dynamic HIF1A regulation during human placental development
Dynamic HIF1A regulation during human placental development
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DOI：
10.1095/biolreprod.106.051557
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发表时间：
2006-07-01
影响因子：
3.6
通讯作者：
Caniggia, Isabella
中科院分区：
文献类型：
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作者：
Ietta, Francesca;Wu, Yuanhong;Caniggia, Isabella
人体胎盘在氧合方面是一个独特的器官，因为它经历了从低氧环境到高氧环境的转变。这种氧分压的生理性转换是胎盘正常发育的先决条件，并涉及低氧诱导因子(HIF)。HIF在低氧条件下稳定并启动基因转录，而在常氧条件下，与von Hippel-Lindau肿瘤抑制蛋白(VHL)相互作用导致HIF1a亚基快速降解。降解需要形成多蛋白复合体(VHLCBC)，并通过产蛋缺陷九(EGLN)家族的成员羟化HIF1a脯氨酸残基。在此，我们研究了人类胎盘发育过程中HIF1a表达的调控机制。HIF1a和VHL在妊娠7~9wk、低氧分压时表达较高，随着胎盘氧分压升高(孕10~12wk)，HIF1a和VHL表达减弱。在胎盘形成早期，HIF1a定位于细胞滋养细胞，而VHL定位于合体滋养层细胞。10~12wk时，细胞滋养层细胞出现VHL，与HIF1a消失相一致。同时，VHL和cullin 2的关联性以及His的泛素化程度最高。EGLN1、EGLN2和EGLN3也以氧依赖的方式暂时表达，在妊娠10-12wk时表达最强。抑制EGLN活性增加了HIF1a在绒毛外植体中的稳定性，并刺激了转化生长因子β3(TGFB3)的表达，这与启动子分析表明HIF1a反式激活TGFB3是一致的。这些数据表明，在胎盘发育过程中，HIF1a受到形成多蛋白VHLCBC复合体的分子的表达和结合以及Pro羟基酶活性的时空变化的调控。
The human placenta is a unique organ in terms of oxygenation as it undergoes a transition from a low to a more oxygenated environment. This physiological switch in oxygen tension is a prerequisite for proper placental development and involves the hypoxia inducible factor (HIF). HIF is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau tumor suppressor protein (VHL) leads to rapid degradation of the HIF1A subunit. The degradation requires formation of a multiprotein complex (VHLCBC) and hydroxylation of HIF1A proline residues via members of the egg-laying-defective nine (EGLN) family. Herein; we have investigated the regulatory mechanisms of HIF1A expression during human placental development. Expression of HIF1A and VHL was high at 7-9 wk of gestation, when oxygen tension is low, and decreased when placental oxygen tension increases (10-12 wk of gestation). During early placentation, HIF1A localized in cytotrophob lasts, while VHL was present in syncytiotrophoblasts. At 10-12 wk, VHL appeared in cytotrophoblast cells, which coincided with the disappearance of HIF1A. At the same time the association of VHL and Cullin 2 as well as ubiquitination of HIM was maximal. EGLN1, EGLN2, and EGLN3 were also temporally expressed in an oxygen-dependent fashion, with greatest mRNA expression at 10-12 wk of gestation. Inhibition of EGLN activity increased HIF1A stability in villous explants and stimulated transforming growth factor beta 3 (TGFB3) expression consistent with promoter analyses showing that HIF1A transactivates TGFB3. These data demonstrate that during placental development, HIF1A is regulated by temporal and spatial changes in expression and association of molecules forming the multi-protein VHLCBC complex as well as prolyl hydroxylase activities.