Bi-phasic regulation of miR-17~92 transcription during hypoxia: Roles of HIF1 and p53 hyperphosphorylation at ser15

Am J Physiol Lung Cell Mol Physiol. 2024 Mar 19. doi: 10.1152/ajplung.00127.2023. Online ahead of print.ABSTRACTWe have reported previously that during hypoxia exposure, the expression of mature miR-17~92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo. Here we investigated the mechanisms regulating this bi-phasic expression of miR-17~92 in PASMC in hypoxia. We measured the level of primary miR-17~92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3%O2, 6 hours) induced the level of primary miR-17~92, while long-term hypoxia exposure (3%O2, 24 hours) decreased its level, suggesting a bi-phasic regulation of miR-17~92 expression at the transcriptional level. We found that short-term hypoxia-induced upregulation of miR-17~92 was HIF1α and E2F1 dependent. Two HIF1α binding sites on miR-17~92 promoter were identified. We also found that long-term hypoxia-induced suppression of miR-17~92 expression could be restored by silencing of p53. Mutation of the p53-binding sites in the miR-17~92 promoter increased miR-17~92 promoter activity in both normoxia and hypoxia. Our findings suggest that the bi-phasic transcriptional regulation of miR-17~92 during hypoxia is controlled by HIF1/E2F1 and p53 in PASMC: during short-term hypoxia exposure, stabilization of HIF1 and induction of E2F1 induces the transcription of miR-17~92; while during long-term hypoxia exposure, hyperphos...

Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - March 19, 2024 Category: Cytology Authors: Miranda R Sun Susana Gonzalez Jason B Huang Qiyuan Zhou Arjun Cherukuri Rohan Adavadkar Hong-Li Yan Shu-Han Sun Guofei Zhou J Usha Raj Tianji Chen Source Type: research