EFFECTS OF AGE ON THE POSTTRANSCRIPTIONAL REGULATION OF CCAAT ENHANCER BINDING-PROTEIN-ALPHA AND CCAAT/ENHANCER BINDING-PROTEIN-BETA ISOFORM SYNTHESIS IN CONTROL AND LPS-TREATED LIVERS/

The CCAAT/enhancer binding protein alpha (C/EBP alpha) and CCAAT/enhan cer binding protein beta (C/EBP beta) mRNAs are templates for the diff erential translation of several isoforms. Immunoblotting detects C/EBP alpha s with molecular masses of 42, 38, 30, and 20 kDa and C/EBP bet a s of 35, 20, and similar to 8.5 kDa. The DNA-binding activities and pool levels of p42(C/EBP alpha) and p30(C/EBP alpha) in control nuclea r extracts decrease significantly whereas the binding activity and pro tein levels of the 20-kDa isoforms increase dramatically with LPS trea tment. Our studies suggest that the LPS response involves alternative translational initiation at specific in-frame AUGs, producing specific C/EBP alpha and C/EBP beta isoform patterns. We propose that alternat ive translational initiation occurs by a leaky ribosomal scanning mech anism. We find that nuclear extracts from normal aged mouse livers hav e decreased p42(C/EBP alpha) levels and binding activity, whereas thos e of p20(C/EBP alpha) and p20(C/EBP beta) are increased. However, tran slation of 42-kDa C/EBP alpha is not down-regulated on polysomes, sugg esting that aging may affect its nuclear translocation. Furthermore, r ecovery of the C/EBP alpha- and C/EBP beta-binding activities and pool levels from an LPS challenge is delayed significantly in aged mouse l ivers. Thus, aged livers have altered steady-state levels of C/EBP alp ha and C/EBP beta isoforms. This result suggests that normal aging liv er exhibits characteristics of chronic stress and a severe inability t o recover from an inflammatory challenge.