Reprogramming of gene expression in postischemic rat liver: induction of proto-oncogenes and hsp 70 gene family.

Steady-state levels of messenger RNA (mRNA) for different members of the heat-shock protein 70 gene family were studied in rat livers reperfused after non-necrogenic ischemia. The expression of constitutive hsc 73 gene decreases during ischemia, returns to normal upon reperfusion, and increases 4 hr after restoration of blood flow. Reperfusion induces the expression of another hsp 70 gene family member (the so-called inducible hsp 70 gene), which remains at high levels for at least 7 hr. The induction of hsp 70 family genes is preceded by activation of the cellular oncogene c-fos, the most prompt change in gene expression detected in reperfused liver. Run-on experiments demonstrate that the increased expression of these genes is largely dependent on activation of transcription. Changes in the amount of c-myc and ornithine decarboxylase mRNA are not evident, while the level of the mRNA for glucose-regulated protein GRP 78 increases later, concurrent with the onset of the acute phase response to surgical trauma. Analysis of polysomal and nonpolysomal fractions from sucrose gradients indicates that in postischemic liver, hsp 70 and hsc 73 mRNA are rapidly engaged on light polysomal or nonpolysomal complexes and are later shifted to polysomes. Albumin mRNA displays the same behavior, indicating that hsp 70 mRNA are not preferentially translated and that increased transcription is the major mechanism for enhanced hsp synthesis in postischemic liver. Damage by active oxygen species, pressure overload, and derangements of protein synthesis is likely to include the causative factors of increased expression of c-fos and the hsp 70 gene family in postischemic reperfused liver.