Abstract
Hypoxia-inducible factor-1 (HIF-1) is the key regulator of cellular adaptive response to hypoxia. Accumulating evidence shows that HIF-1 induces some non-coding RNAs (ncRNAs) including lncRNAs and miRNAs to modulate its own activity, enclosing several feedback loops. How the two classes of ncRNAs are orchestrated in the HIF-1-dependent adaptive response to hypoxia is poorly understood. By selecting lincRNA-p21 and miR-155 as the representatives, we develop an integrated model of the HIF-1 network comprising interlinked positive and negative feedback loops to clarify the interplay between the two ncRNAs in the hypoxic response. By numerical simulations, we find that coordination of lincRNA-p21 and miR-155 shapes the adaptive dynamics of HIF-1α: lincRNA-p21 induction in the early phase stimulates the upregulation of HIF-1α via stabilizing it, while miR-155 induction in the late phase promotes the recovery of HIF-1α via enhancing the degradation of its mRNA. Moreover, HIF-1α-induced PHD2 plays an auxiliary role in the decline of HIF-1α. In addition, lincRNA-p21 and miR-155 modulate each other via regulating HIF-1α activity. Together, lincRNA-p21 and miR-155 coordinate in modulating HIF-1α dynamics, and our work may shed light on the role for ncRNAs in the cellular adaptation to hypoxia.
Highlights
Hypoxia plays significant roles in human physiology and diseases including cancer (Koh and Powis, 2012)
We found that lincRNA-p21 and miR-155 are sequentially induced during hypoxia
LincRNA-p21 promotes the rising of HIF-1α by stabilizing it in the early phase, while miR-155 promotes the recovery of HIF-1α in the late phase by facilitating the degradation of its mRNA
Summary
Hypoxia plays significant roles in human physiology and diseases including cancer (Koh and Powis, 2012). Hypoxia-inducible factor-1 (HIF-1) is the key mediator of the cellular adaption to hypoxia (Schofield and Ratcliffe, 2004). HIF-1α is hydroxylated by prolyl hydroxylases (PHDs) on Pro402 and Pro564, and these modifications facilitate the binding of HIF-1α to VHL (von Hippel-Lindau), promoting the ubiquitin-dependent proteasomal degration of HIF-1α (Ohh et al, 2000; Jaakkola et al, 2001). The hydroxylase factor inhibiting HIF-1 (FIH-1) hydroxylates HIF-1α on Asn803 to repress its transcriptional activity via preventing the recruitment of coactivator p300/CBP (Mahon et al, 2001). PHDs and FIH-1 are deactivated so that HIF-1α is stabilized and translocates to the nucleus to form a transcriptional complex with HIF-1β (Maxwell et al, 2001).
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