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Fig. 1 | Journal of Biomedical Science

Fig. 1

From: Signaling in and out: long-noncoding RNAs in tumor hypoxia

Fig. 1

Regulations of HIF-1 activity by HALs. a Regulation of HIF-1. Under normoxia (green arrows), HIF-1α subunit is hydroxylated by PHDs (prolyl hydroxylase domain proteins). Hydroxylation residues within HIF-1α facilitates interaction of HIF-1α with the E3 ubiquitin ligase VHL protein, targeting HIF-1α for polyubiquitination and subsequent proteasome-dependent degradation. Upon hypoxia (red arrows), the PHDs and other prolyl hydroxylases are inhibited, leading to HIF-1α stabilization and translocation into nucleus. After dimerization with its transcriptional partner HIF-1β and recruitment of co-activators (e.g. CBP/p300), the HIF-1 heterodimer binds the HRE (hypoxia response element) of target genes to regulate transcription. b Transcriptional co-activator. Hypoxia-induced LncHIFCAR could directly interact with HIF-1α and facilitate the recruitment of HIF-1α and p300 cofactor to the target loci, thereby upregulating HIF-1 target genes. c Recruitment of transcription factor. HIF-1α-induced LncRNA-MTA2TR could recruit ATF3 to the promoter area of MTA2, thereby transcriptionally upregulating the expression of oncogenic MTA2. MTA2 can subsequently enhance HIF-1α protein accumulation via deacetylation, forming a feedback loop to amplify HIF-1 signaling. d mRNA stability control. The expression of lncRNA-LET is repressed through hypoxia-induced HDAC3, which reduces the histone H3 and H4 acetylation at the LncRNA-LET promoter. Decreased lncRNA-LET expression reduces the lncRNA-LET–mediated degradation of HIF-1α negative regulator, NF90, leading to HIF-1α accumulation. e ceRNA/miRNA sponge. Hypoxia-induced H19 could upregulate HIF-1α expression by absorbing miRNA let-7 and nullifying let-7-mediated HIF1A mRNA suppression. f Molecular decoy. lincRNA-p21 is able to disrupt the interaction between HIF-1α and its negative regulator VHL via separate binding to both HIF-1α and VHL, thereby blocking VHL-dependent HIF-1α degradation. g Complex scaffold. LINK-A-mediated recruitment and enzymatic activation of BRK and LRRK2 kinases could facilitate phosphorylation of HIF-1α at specific residues. These phosphorylation modifications prevent subsequent HIF-1α degradation and enhance the association between HIF-1α and cofactor p300, thereby upregulating HIF-1 target genes. See text for a more detailed discussion

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