Section 35
Chapter 34,798

Effect of hypoxia on translation initiation factors in the C2C12 skeletal muscle cell line over time

Clark, L.; Fillenwarth, M.J.; Shen, W.; Boyle, D.W.

FASEB Journal 17(4-5): Abstract 819


ISSN/ISBN: 0892-6638
Accession: 034797705

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Translation initiation is regulated through formation of the 43S ribosomal subunit, mediated through eukaryotic initiation factor 2 (eIF2) activity, and by recruitment of mRNA to the ribosome, mediated by formation of the eIF4F complex. We investigated the effect of hypoxia on the phosphorylation state of the eIF's identified to be primary components in the rate-limiting steps of translation initiation. We hypothesized that culturing differentiated C2C12 skeletal muscle cells under hypoxic conditions would a) increase phosphorylation of eIF2a, leading to decreased eIF2 activity; and b) decrease phosphorylation of 4E-BP1, inhibiting the formation of the eIF4F complex. Differentiated C2C12 cells were incubated at 1%, 5%, or 21% oxygen for 1, 6, 24, or 48 hours. Phosophorylation of eIF2a (p-eIF2a) was increased in cells exposed to 1% oxygen. This effect was maximal at 24 hours. Hypoxia decreased 4E-BP1 phosphorylation. Consequently, hypoxia was associated with an increase in the association of 4E-BP1 with eIF4E. The decrease in 4E-BP1 phosphorylation was related to both the severity and the duration of the hypoxic exposure. We conclude that exposure of this differentiated skeletal muscle cell line to hypoxia results in inhibition of translation initiation via alterations in the phosphorylation states of the eIF's that are the primary components of the two rate-limiting steps. These cellular changes become more pronounced with time and with increasing severity of hypoxia.

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