Molecular cloning of two C/EBP-related proteins that bind to the promoter and the enhancer of the α₁-fetoprotein gene. Further analysis of C/EBPβ and C/EBPγ

Abstract

In an attempt to identify proteins that may regulate alpha 1-fetoprotein (AFP) gene expression, we screened a cDNA expression library from neonatal rat liver with two essential cis-elements of the AFP promoter and enhancer. We isolated two cDNAs which were found to correspond to leucine zipper proteins of the CC-AAT/enhancer binding protein (C/EBP) family: C/EBP beta and C/EBP gamma. The three related proteins C/EBP alpha, beta and gamma bind with indistinguishable specificity to multiple DNA sites in the promoter and the enhancer of the AFP gene. In addition, C/EBP beta and C/EBP gamma readily heterodimerize with each other as well as with C/EBP alpha. The mRNAs coding for C/EBP beta and C/EBP gamma are expressed in a wider variety of rat tissues than C/EBP alpha mRNA, including yolk sac and fetal liver. The steady-state levels of C/EBP alpha, beta and gamma mRNAs increase during liver development, in parallel with their respective gene transcriptional rates. The high levels of C/EBP beta and gamma mRNAs in rat yolk sac and fetal liver, where C/EBP alpha is poorly expressed, suggest that C/EBP beta and/or gamma could be preponderant or early regulators of the AFP gene in these tissues.

C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

“…C/EBPγ is ubiquitously expressed and was first identified by its affinity for cis-regulatory sites in the immunoglobulin heavy chain promoter and enhancer (26). Structurally, C/EBPγ is characterized by the absence of transactivation domains, although it retains the basic region and the leucine zipper domains, required for DNA binding and homo/heterodimerization, respectively (27,28). C/EBPγ alone neither activates nor represses transactivation; however, C/EBPγ can inhibit transcriptional activation by other C/EBP members in a cell-specific manner (27,29).…”

C/EBP regulates the promoter of the eosinophil-derived neurotoxin/RNS2 gene in human eosinophilic cells

“…C/EBP␥ is ubiquitously expressed, with the highest levels found in non-differentiated progenitor cells. C/EBP␥ lacks transcriptional activation elements, suggesting a dominant-negative regulation of C/EBP transactivation in undifferentiated cells [26,27]. C/EBP⑀ is essential for terminal differentiation and functional maturation of committed granulocyte progenitor cells [28,29].…”

Multiple forms of C/EBP beta bind the EFII enhancer sequence in the Rous sarcoma virus long terminal repeat.

“…Thus, although C/EBPa has been shown to bind the EFII site in the RSV LTR enhancer (63), it is likely that other C/EBP family members with a wider tissue distribution are involved in activating EFII-mediated transcription in many cell types. Other C/EBP family members include the following: C/EBPI3 (9), also known as NF-IL6 (1), LAP (14), IL-6DBP (56), AGP/EBP (10), CRP2 (78), rNFIL-6 (45), and possibly N-FM (31); C/EBP8 (9), also called CRP3 (78), NF-IL6p (33), and CELF (29); C/EBP-y (9,73), originally called Ig/EBP-1 (59); al/EBP (7); CRP1 (78); and CHOP-10 (60).…”