Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Sci Rep. 2019 Jul 22;9(1):10599. doi: 10.1038/s41598-019-47071-1.
The transcription factor HIF-1 induces the expression of genes that are essential for cell survival and oxygen homeostasis in hypoxic conditions. The prolyl isomerase Pin1 plays a role in the regulation of HIF-1α. However, the mechanism by which Pin1 controls HIF-1α remains controversial. Surprisingly, we here show that a PIN1 transcript downregulates HIF-1α as a long non-coding RNA. Pin1-silencing siRNAs augmented the hypoxia-induced expression of HIF-1α, thereby upregulating the expression of HIF-1 target genes. However, the overexpression of Pin1 protein did not inhibit the hypoxic expression of HIF-1α. Pin1 restoration in Pin1-depleted cells also failed to reverse the induction of HIF-1α by Pin1 knockdown. Unexpectedly, HIF-1α was found to be induced by both siRNAs for PIN1 transcript variants 1/2 and that for PIN1 transcript variants 2/3, indicating that the PIN1 transcript variant 2 (PIN1-v2) is responsible for HIF-1α induction. Mechanistically, PIN1-v2, which is classified as a long non-coding RNA due to early termination of translation, was evaluated to inhibit the transcription of HIF1A gene. In conclusion, PIN1-v2 may function in balancing the HIF-1-driven gene expression under hypoxia.
转录因子 HIF-1 诱导在缺氧条件下对细胞存活和氧平衡至关重要的基因表达。脯氨酰异构酶 Pin1 在 HIF-1α 的调节中发挥作用。然而，Pin1 控制 HIF-1α 的机制仍存在争议。令人惊讶的是，我们在这里表明，PIN1 转录本作为长非编码 RNA 下调 HIF-1α。Pin1 沉默 siRNA 增强了缺氧诱导的 HIF-1α 表达，从而上调了 HIF-1 靶基因的表达。然而，Pin1 蛋白的过表达并没有抑制 HIF-1α 的缺氧表达。在 Pin1 耗尽的细胞中恢复 Pin1 也未能逆转 Pin1 敲低对 HIF-1α 的诱导。出乎意料的是，发现 HIF-1α 被两种针对 PIN1 转录本变体 1/2 的 siRNA 和针对 PIN1 转录本变体 2/3 的 siRNA 诱导，表明 PIN1 转录本变体 2（PIN1-v2）负责 HIF-1α 诱导。从机制上讲，由于翻译早期终止，被归类为长非编码 RNA 的 PIN1-v2 被评估为抑制 HIF1A 基因的转录。总之，PIN1-v2 可能在缺氧下平衡 HIF-1 驱动的基因表达中发挥作用。
