Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase of liver regeneration.
In regenerating liver, a physiologically normal model of cell growth, LRF-1, JunB, c-Jun, and c-Fos among Jun/Fos/LRF-1 family members are induced posthepatectomy. In liver cells, high levels of c-Fos/c-Jun, c-Fos/JunB, LRF-1/c-Jun, and LRF-1/JunB complexes are present for several hours after the G0/G1 transition, and the relative level of LRF-1/JunB complexes increases during G1. We provide evidence for dramatic differences in promoter-specific activation by LRF-1- and c-Fos-containing complexes. LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. LRF-1/c-Jun, c-Fos/c-Jun, and c-Fos/JunB activate specific AP-1 and ATF site-containing promoters, and in contrast, LRF-1/JunB potently represses c-Fos- and c-Jun-mediated activation of these promoters. Repression is dependent on a region in LRF-1 that includes amino acids 40 to 84 (domain R) and the basic/leucine zipper domain. As the relative level of LRF-1/JunB complexes increases posthepatectomy, c-Fos/Jun-mediated ATF and AP-1 site activation is likely to decrease with simultaneous transcriptional activation of the many liver-specific genes whose promoters contain cyclic AMP response element sites. Thus, through complex interactions among LRF-1, JunB, c-Jun, and c-Fos, control of delayed gene expression may be established for extended times during the G1 phase of hepatic growth.
Hsu
J C
JC
Department of Human Genetics, University of Pennsylvania School of Medicine, Philadelphia 19104-6145.
Bravo
R
R
Taub
R
R
D016475:3T3 Cells; D051700:Activating Transcription Factor 3; D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics; D005786:Gene Expression Regulation; D007328:Insulin / Q000494:pharmacology; D016350:Leucine Zippers / Q000235:genetics; D008115:Liver Regeneration / Q000235:genetics; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D015533:Transcriptional Activation
D051700:Activating Transcription Factor 3; D004268:DNA-Binding Proteins; D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; C068616:liver regeneration factor 1