CHARACTERIZATION OF ENDOGENOUS HYPDXIA-INDUCED TRANSCRIPTIONAL REPRESSOR HIF-3ALPHA

内源性缺氧诱导的转录抑制子 HIF-3ALPHA 的表征

• 批准号: 18590071
• 负责人: HARA Shuntaro
• 金额: $ 2.55万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590071/
• 关键词: HYPDXIA; HYPDXIA-INDUCIBLE FACTOR; TUMOR ANGIOGENESIS; TRANSCRIPTIONAL REGULATION; がんの悪性化; 前立腺がん

Hypoxia-inducible factor (HIF) is an important transcriptional factor that is activated when mammalian cells experience hypoxia, a tumor microenvironmental condition that plays a pivotal role in tumor progression and treatment. HIF consists of oxygen-sensitive HIF-α and constitutively expressed HIF-β subunits. The recently identified third member of the human HIF-α, HIF-3α, produces multiple splicing variants. Here we cloned cDNA for one of the splicing variants of human HIF-3α, HIF-3α2, from human kidney and examined its characteristics. HIF-3α2, as well as the first identified HIF-3α variant HIF-3α1, localized in the nucleus and was stabilized under hypoxia when ectopically expressed in COS-7 cells. However, reporter gene analysis showed that HIF-3α2 failed to activate HIF-mediated transcription and conversely suppressed it, although HIF-3a1 with an N-terminal domain identical to HIF-3α2 had the ability to activate it. C-terminal deletion analysis revealed that the C-terminal moiety of HIF-3α2 masked its own transcriptional activity. We further showed that overexpression of HIF-3α2 in renal carcinoma VMRC inhibited both hypoxia-inducible gene expression in vitro and growth as xenografts in vivo. These results indicated that HIF-3α2, which is stabilized under hypoxia, functions as a negative regulator of hypoxia-inducible gene expression in a novel feedback mechanism.

缺氧诱导因子 (HIF) 是一种重要的转录因子，在哺乳动物细胞缺氧时被激活，缺氧是一种在肿瘤进展和治疗中发挥关键作用的肿瘤微环境条件，HIF 由氧敏感的 HIF-α 和组成型表达的 HIF- 组成。最近鉴定的人类 HIF-α 的第三个成员 HIF-3α 产生多种剪接变体，我们克隆了人类剪接变体之一的 cDNA。 HIF-3α、HIF-3α2 来自人肾，并检查了其特征 HIF-3α2 以及第一个鉴定的 HIF-3α 变体 HIF-3α1，定位于细胞核，在 COS-7 中异位表达时在缺氧下稳定。然而，报告基因分析表明，尽管 HIF-3a1 的 N 端结构域与 HIF-3α2 相同，但 HIF-3α2 未能激活 HIF 介导的转录，反而抑制了它。 HIF-3α2 具有激活它的能力，分析表明 HIF-3α2 的 C 端部分掩盖了其自身的转录活性，我们进一步表明 HIF-3α2 在肾癌 VMRC 中的过度表达抑制了缺氧诱导。体外基因表达和体内异种移植物生长这些结果表明，在缺氧条件下稳定的 HIF-3α2 发挥负调节作用。一种新的反馈机制中缺氧诱导的基因表达。

项目成果

Characterization of human splice variants of hypoxia-inducible factor-3α

缺氧诱导因子 3α 的人类剪接变体的表征

• 发表时间: 2006
• 作者: Hara;S.;Kondo;Y.;Kudo;I.
• 通讯作者: I.

Cross-talk between the androgen receptor and hypoxia-inducible factor-1 signaling in human prostate cancer cells

人前列腺癌细胞中雄激素受体与缺氧诱导因子 1 信号传导之间的串扰

• 发表时间: 2007
• 作者: Hara;S.;Kondo;Y.;Kudo;I.
• 通讯作者: I.

Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells

• DOI: 10.1158/1541-7786.mcr-06-0226
• 发表时间: 2007-04-01
• 期刊: MOLECULAR CANCER RESEARCH
• 影响因子: 5.2
• 作者: Horii, Kou;Suzuki, Yasutomo;Hara, Shuntaro
• 通讯作者: Hara, Shuntaro

Role of proinflammatory prostaglandin E2 in bladder tumor progression

促炎性前列腺素 E2 在膀胱肿瘤进展中的作用

• 发表时间: 2007
• 作者: Hara;S.
• 通讯作者: S.

Role of prostaglandin E2 receptor EP1 in bladder carcinogenesis

前列腺素E2受体EP1在膀胱癌发生中的作用

• 发表时间: 2007
• 作者: Hara;S.;et. al.
• 通讯作者: et. al.