Hypoxia increases the association of 4E‐binding protein 1 with the initiation factor 4E in isolated rat hepatocytes

Abstract

Incubation of hepatocytes under hypoxia increases binding of translation initiation factor eIF-4E to its inhibitory regulator 4E-BP1, and this correlates with dephosphorylation of 4E-BP1. Rapamycin induced the same effect in aerobic cells but no additive effect was observed when hypoxic cells were treated with rapamycin. This enhanced association of 4E-BP1 with eIF-4E might be mediated by mTOR. Nevertheless, only hypoxia produces a rapid inhibition of protein synthesis. Although hypoxia might be signalling via the rapamycin-sensitive pathway by changing eIF-4E availability, such a pathway is unlikely to be responsible for the depression in overall protein synthesis under hypoxia.z 1999 Federation of European Biochemical Societies.

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

“…In their underphosphorylated forms, the 4E-BPs bind eIF4E with high affinity and thus prevent eIF4F formation. A role for this pathway in controlling translation during hypoxia is supported by reports that both moderate (28,30,62,63) and severe (24) hypoxia cause dephosphorylation of 4E-BP1 and a corresponding increase in the association of this protein with eIF4E. Recent data from Connolly et al have functionally linked 4E-BP1 to the regulation of translation during moderate hypoxia.…”

Stress and mTORture signaling

“…This early response dominates the first phase in response to hypoxia. Chronic hypoxia leads to the accumulation of hypophosphorylated 4E-BP and hence increased binding to eIF4E (Tinton and Buc-Calderon, 1999;Connolly et al, 2006). mTOR activity is downregulated under acute low oxygen regimes in an HIF-1-and ATP level-independent manner, as shown by a reduction in phospho-S6K/S6 and phospho-4E-BP phosphorylation (Arsham et al, 2003;Brugarolas et al, 2004;Liu et al, 2006).…”

Regulation of Transcription and Translation by Hypoxia

“…Of note, global protein translation that involves the 5'-m 7 -GTP cap is inhibited during hypoxia, whereas translation by IRE is spared from downregulation. 3,[45][46][47] Moreover, hypoxia is known to modulate two critical steps in cap-dependent translation initiation, namely the assembly of active eukaryotic initiation factor eIF4F complex (eIF4E, eIF4G and eIF4A) and the eIF2-GTP/Met-tRNA ternary complexes by changing phosphorylation states of eIF4E binding protein (4E-BP1) and eIF2α (Fig. 2).…”

“…47 Hypophosphorylated 4E-BP1 binds to eIF4E with relatively high affinity and prevents the assembly of eIF4F. 43,46,47 The effect of hypoxia on 4E-BP1 and p70 S6K is dominant to stimulation by insulin, leucine, and phorbol ester like Phorbol-12-Myristate-13-Acetate. Interestingly, while HIF is necessary for the majority of transcriptional activation during hypoxia, HIF is dispensable for the effects of hypoxia on 4E-BP1 and p70 S6K .…”