CCAAT/enhancer binding protein ? (C/EBP?) is an important mediator of mouse C/EBP? protein isoform production

Both CCAAT/enhancer binding protein α (C/EBPα) and C/EBPβ are intronless, yet can create various N–terminally truncated protein products with distinct DNA binding and transactivation potentials. These proteins can be generated via two distinct mechanisms, one translational and the other post–translational. In the translational mechanism, there is alternative translational start site selection of the different AUG codons present in the single messenger RNA (mRNA) species via a process of leaky ribosome scanning. Additionally, a post–translational method of isoform formation, through specific proteolytic cleavage of the full length protein has also been described. In this manuscript, we present evidence that the production of C/EBPβ protein isoforms in the neonatal mouse liver is regulated by C/EBPα. In C/EBPα knockout mice, the predominant C/EBPβ proteins are the larger 38– and 35–kd isoforms, whereas wild–type animals primarily possess the smaller 21– and 14–kd isoforms. These C/EBPα–dependent differences are liver specific, not present in lung or adipose tissues, and present at day 18 of development. Additionally, we show that induction of C/EBPα expression leads to an increase in the production of the 21–kd C/EBPβ isoform in cell culture studies. As the various C/EBPβ protein isoforms have different transcriptional capabilities, it is important to understand the regulation of the production of these isoforms. Our observations suggest a novel role for the C/EBPα transcription factor in this process.