Human C/EBPα is an intronless gene located on the minus strand of chromosome 19q.

The C/EBPa mRNA (RNA messenger) consists of a short 5 unstranslated region (5-UTR), a unique protein coding sequence (CDS) and a long 3-UTR (Hendricks-Taylor et al., 1992).

Human C/EBPα mRNA gives rise to two protein products by using two different translation starting sites (Figure 1 and 2) (Calkhoven et al., 2000). Compared to full-length C/EBPA protein, P42, the shorter P30 isoform lacks N-terminal 117 amino acids (Lin et al., 1993).
As a transcription factor, C/EBPA protein consists of DNA-binding domain (DBD) in its carboxyl-terminal (C-terminal), which is conserved between C/ebp family members (Leutz et al., 2011). The highly conserved C-terminus includes the basic DNA binding leucine zipper domain (bZip). The bZip domain in turn consists of a basic region that represents the DNA binding domain (DBD), the fork domain and the leucine zipper domain (LZ). The bZip domain is indispensable for homodimerization and heterodimerization with other members of the C/EBP family. This region is also involved in the interaction with other transcription factors (e.g. E2F, PU.1, c-JUN, RUNX1 and ETS1) (McNagny et al., 1998; Yamaguchi et al., 1999; Ramji and Foka, 2002; Nerlov, 2004; Koschmieder et al., 2005; Leutz et al., 2011).
The N-terminus of C/EBPa consists of three transactivation domains (TA), which can interact with components of the transcriptional machinery (e.g. CBP/P300, TBP/TFIIB) (Nerlov and Ziff, 1995; Kovacs et al., 2003; Schwartz et al., 2003), cell cycle regulators (e.g. E2F, CDK2, CDK4) (Porse et al., 2001; Porse et al., 2006) and chromatin remodellers (e.g. SWI/SNF) (Pedersen et al., 2001).

C/EBPa is mainly expressed in terminally differentiated cells, such as mature adipocytes and myelomonocytic cells. C/EBPa is also found expressed in skin, intestine, lung, adrenal gland, mammary gland, ovary, prostate, placenta (Oh and Smart, 1998; Birkenmeier et al., 1989).

C/EBPa protein is localized in nucleus.

C/EBPa homozygous null mice lack white adipose tissues (Wang et al., 1995), as well as mature granulocytes and granulocyte-macrophage precursors (Zhang et al., 1997; Heath et al., 2004). In addition, forced expression of C/EBPa can direct uncommitted progenitors to differentiate into adipocytes and granulocytes (Freytag et al., 1994; Radomska et al., 1998; Nerlov et al., 1998). Further studies suggest that C/EBPa plays important roles in lineage determination by activating lineage-specific genes (Nerlov, 2004; Graf and Enver, 2009).
In hematopoiesis, C/EBPa is one of the key factors driving myeloid cell differentiation from hematopoietic stem cells by interacting with other proteins, such as the ETS family transcription factor PU.1, the ATP dependent chromatin remodeling complex SWI/SNF, the DNA modifying enzyme TET2 (McNagny et al., 1998; Koschmieder et al., 2005; Leutz et al., 2011; Kallin et al., 2012). Ectopic expression of C/EBPa leads to cell cycle arrest via direct interaction with the key cell cycle regulators CDK2/4 and E2F (Porse et al., 2001; Porse et al., 2006). The N-terminal truncated form of C/EBPa, P30, has been shown to act as a dominant negative regulator of the full-length form, P42. Modulation of P30 expression level in mice can alter normal adipogenesis and granulopoiesis (Kirstetter et al., 2008).
Notably, ectopic expression of C/EBPa in B and T-lymphocyte precursors results in transdifferentiation into functional macrophages (Xie et al., 2004; Laiosa et al., 2006; Bussmann et al., 2009; Di Tullio et al., 2011; Kallin et al., 2012). Interestingly, C/EBPa mediated conversion of B lymphoma cells into macrophages impairs significantly its tumorigenicity, providing a novel strategy for lymphoma treatment (Rapino et al., 2013). Moreover, a recent study showed that transient C/EBPa expression is also capable of facilitating the conversion of B cells into induced pluripotent stem cells (iPS cells) (Di Stefano et al., 2014).
Moreover, C/EBPa has been shown involved in lung development and airway epithelial differentiation (Cassel et al., 2000a; Cassel et al., 2000b; Cassel et al., 2002). The conditional deletion of C/EBPa gene in respiratory epithelium results in respiratory arrest and death soon after birth. This phenotype is associated with proliferation of immature type II alveolar cells, which causes epithelial expansion and loss of air space (Martis et al., 2006; Basseres et al., 2006).

C/EBPa belongs to the CCAAT/enhancer binging protein family and is highly conserved across vertebrate species. Sequence alignments show that C/EBP members share several conserved regions including the bZip and transactivation domains (Leutz et al., 2011).

Mutations of the C/EBPα gene have been detected in 7%-15% of Acute Myeloid Leukemia (AML) (Pabst et al., 2001b; Preudhomme et al., 2002; Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2003; Snaddon et al., 2003; Frohling et al., 2004; Lin et al., 2005), around 4% of Myelodysplastic Syndrome (MDS) and Chronic Myeloid Leukemia (CML) (Shih et al., 2005). In addition, two familial cases of AML harboring C/EBPA mutations have been reported (Smith et al., 2004; Renneville et al., 2009).

Germ line mutations of C/EBPα have been described for two familial cases of AML. In one Inherited acute myeloid leukemia case, a heterozygous deletion of cytosine 212 has been reported (Smith et al., 2004). Recently, the second family contained a heterozygous insertion of cytosine at nucleotide 217 (Renneville et al., 2009). These mutations result in frameshifts, leading to a premature termination of full-length C/EBPa P42 isoform translation. Nonetheless, the alternative C/EBPa P30 isoform translation could be potentially privileged. P30 isoform has dominant-negative activity on the full-length P42 isoform.

It has been shown that 7%-15% of AML harbor somatic mutations of the C/EBPα gene (Pabst et al., 2001b; Preudhomme et al., 2002; Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2003; Snaddon et al., 2003; Frohling et al., 2004; Lin et al., 2005). In addition, C/EBPα mutations have been detected in MDS and CML patient samples. These mutations can be basically divided into two categories: C-terminal in-frame ins/del mutations altering C/EBPA DNA-binding activities, and N-terminal out-of-frame ins/del mutations impairing translation of full-length P42 isoform and leading aberrant expression of P30 isoform, which has dominant-negative activity on P42 isoform. The majority of leukemias with biallelic C/EBPA mutations harbor one allele with C-terminal mutations and the other one with N-terminal mutations. Tumors with homozygous N-terminal or C-terminal mutations are relatively rare.