Bi-phasic Regulation of miR-17~92 in Pulmonary Arterial Smooth Muscle Cells (PASMC)
Session Number
MEDH 35
Advisor(s)
Dr. Tianji Chen, University of Illinois Chicago
Discipline
Medical and Health Sciences
Start Date
17-4-2024 10:25 AM
End Date
17-4-2024 10:40 AM
Abstract
We have reported previously that during hypoxia exposure, the expression of mature miR- 17~92 was first upregulated and then downregulated in 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, hyperphosphorylation of p53 suppresses the expression of miR-17~92.
Bi-phasic Regulation of miR-17~92 in Pulmonary Arterial Smooth Muscle Cells (PASMC)
We have reported previously that during hypoxia exposure, the expression of mature miR- 17~92 was first upregulated and then downregulated in 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, hyperphosphorylation of p53 suppresses the expression of miR-17~92.