Ccaat-enhancer-binding proteins

CCAAT-enhancer-binding proteins (or C/EBPs) are a family of transcription factors that are composed of six members C/EBP α to C/EBP ζ. They promote the expression of certain proteins through interaction with DNA.

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C/EBP proteins interact with the CCAAT (cytidine-cytidine-adenosine-adenosine-thymidine) box motif which is present in several gene promoters. They are characterized by a highly conserved basic-leucine zipper (bZIP) domain at the C-terminus. This domain is involved in dimerization and DNA binding like other transcription factors of the leucine zipper family like c-Fos and Jun. C/EBPs bZIP domain structure is composed of an α-helix that forms a coiled coil structure when it dimerizes. The different members of C/EBP family can form homodimers, heterodimers with another form of the C/EBPs and with other transcription factors that may or may not contain the leucine zipper domain. The dimerization is requested for the activity of C/EBPs to bind specifically to DNA through a palindromic sequence in the major groove of the DNA. The C/EBP proteins also contain activation domains at the N-terminus and regulatory domains.

These proteins are found in hepatocytes, adipocytes, hematopoietic cells, spleen, kidney, brain and many others organs. C/EBPs proteins are involved in different cellular responses like in the control of cellular proliferation, growth and differentiation, metabolism, immunology and many others. All the members of the C/EBP family, except C/EBPγ, can induce transcription, through their activation domains, by interacting with components of the basal transcription apparatus. Their expression is regulated at multiple levels through hormones, mitogens, cytokines, nutrients, etc.

The C/EBPα, -β, -γ and -δ genes are intronless and C/EBPε and -ζ have respectively two and four exons that lead in the case of C/EBP ε to four isoforms due to an alternative use of promoters and splicing. For C/EBPα and -β, different sizes of polypeptides can be produced by alternative use of initiation codons due to weak ribosome scanning mechanisms. The mRNA of C/EBPα can lead to two polypeptides and for C/EBPβ three different polypeptides are made: LAP* (38 kDa), LAP (35 kDa) and LIP (20 kDa). The most translated isoform is LAP, then LAP* and LIP; the latter can act as an inhibitor of the other C/EBPs by forming non-functional heterodimers.

This protein is expressed in the mammalian nervous system and has many implications in the nerve cells. C/EBPβ plays a role in neuronal differentiation, in learning and memory process, glial or neuronal cell functions and neurotrophic factory expression.

The regulation of C/EBPβ is exerted in many manners, phosphorylation, acetylation, activation and repression via others transcription factors, oncogenic elements or chemokines, autoregulation, etc. C/EBPβ can interact with different proteins like CREB, NF-κB and others that lead to a trans-activation potential. Or phosphorylation can have an activation or a repression effect. For example, phosphorylation of the Threonine 235 in human or of the Threonine 188 in mouse and rat is important for its trans-activation capacity or phosphorylation(s) in its regulatory domain modulate its function.

References

• Ramji, D. P. & Foka P., CCAAT/enhancer-binding proteins: structure, function and regulation, Biochem. J. 365:561-575 (2002).