CCAAT-enhancer-binding proteins (or C/EBPs) are a family of transcription factors, composed of six members called C/EBP α to C/EBP ζ. They promote the expression of certain genes through interaction with their promoter. Once bound to DNA, C/EBPs can recruit so-called coactivators (such as CBP, see ref. 2) that, in turn, can open up chromatin structure, or recruit basal transcription factors.

C/EBP proteins interact with the CCAAT (cytidine

Cytidine

Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...

-cytidine-adenosine-adenosine-thymidine

Thymidine

Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...

) 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

Leucine zipper

A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...

 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

Protein dimer

In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

. 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 required 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 hepatocyte

Hepatocyte

A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...

s, adipocyte

Adipocyte

However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...

s, hematopoietic cells, spleen

Spleen

The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

, kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 and many others organs. C/EBPs proteins are involved in different cellular responses like in the control of cellular proliferation, growth and differentiation, metabolism

Metabolism

Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

, immunology

Immunology

Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

 and many others. All the members of the C/EBP family, except C/EBPγ that lacks transcriptional activation domain, can induce transcription, through their activation domains, by interacting with components of the basal transcription apparatus. Their expression is regulated at multiple levels through hormone

Hormone

A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

s, mitogen

Mitogen

A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....

s, cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s, nutrients, etc.

The C/EBPα, -β, -γ and -δ genes are intron

Intron

An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...

less 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

Ribosome

A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

 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

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 of the other C/EBPs by forming non-functional heterodimers.

This protein is expressed in the mammalian nervous system

Nervous system

The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...

 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.

C/EBPβ function is regulated via multiple mechanisms: phosphorylation

Phosphorylation

Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

; acetylation

Acetylation

Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...

; activation and repression via other transcription factors, oncogenic elements or chemokines; autoregulation, etc. C/EBPβ can interact with different proteins, such as CREB

CREB

CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....

, NF-κB and others, leading to a trans-activation potential. Phosphorylation of C/EBPβ can have an activation or a repression effect. For example, phosphorylation of threonine 235 in human C/EBPβ, or of threonine 188 in mouse and rat C/EBPβ, is important for C/EBPβ trans-activation capacity; phosphorylation(s) of C/EBPβ in its regulatory domain can also modulate its function.

Role in Adipogenesis

C/EBPβ and δ are transiently induced during the early stages of adipocyte differentiation (adipogenesis), whereas C/EBPα is upregulated during the terminal stages of adipogenesis; each plays an important role in this process, as demonstrated from in vitro and in vivo studies. For example, murine embryonic fibroblasts (MEFs) from mice lacking both C/EBPβ and δ show impaired adipocyte differentiation in response to adipogenic stimuli [4]. In contrast, ectopic expression of C/EBPβ and δ in 3T3-L1 preadipocytes promotes adipogenesis, even in the absence of adipogenic stimuli [5, 6]. C/EBPβ and δ promote adipogenesis, at least in part, by inducing the expression of the 'master' adipogenic transcription factors, C/EBPα and PPARγ.

C/EBPα is required for both adipogenesis and normal adipocyte function. For example, mice lacking C/EBPα in all tissues except the liver (to avoid postnatal lethality) show abnormal adipose tissue formation [7]. Moreover, ectopic expression of C/EBPα in various fibroblast cell lines promotes adipogenesis [8]. It is likely that C/EBPα promotes adipogenesis by inducing the expression of PPARγ [9].

Role in Osteoporosis

C/EBPβ has recently been found to have a role in osteoporosis

Osteoporosis

Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 development. The full-length isoform of the C/EBPβ protein (LAP)activates the MafB

MAFB

MAFB can refer to:* MAFB, a human gene that encodes the MafB transcription factor* March Joint Air Reserve Base * Maxwell Air Force Base in Montgomery, Alabama* Minot Air Force Base in Minot, North Dakota...

 gene, whereas the short isoform (LIP) suppress it; MafB gene activation suppress osteoclastogenisis (i.e., formation of osteoclasts). Thus upregulation of LAP diminishes the number of osteoclasts (which, in turn, weakens the osteoporotic process), whereas upregulation of LIP does the opposite (and increases the loss of bone mass).

The LAP/LIP balance is determined by mTOR protein. Inhibition of mTOR can stop osteoclast activity.