CCAAT-enhancer-binding proteins

C/EBPα bZip domain bound to DNA. PDB entry 1nwq^[1]

CCAAT-enhancer-binding proteins (or C/EBPs) is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C/EBPs can recruit so-called co-activators (such as CBP^[2][3]) that in turn can open up chromatin structure or recruit basal transcription factors.

Contents

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  1 Function
  


• 
  2 Gene transcription
  


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  3 Regulation
  


• 
  4 Clinical significance
  
  
  
  • 
    4.1 Role in adipogenesis
    
  
  
  • 
    4.2 Role in osteoporosis
    
  
  
  
  


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  5 References
  


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  6 External links
  

Function

C/EBP proteins interact with the CCAAT (cytosine-cytosine-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, as are other transcription factors of the leucine zipper domain-containing family (c-Fos and c-jun). The bZIP domain structure of C/EBPs is composed of an α-helix that forms a "coiled coil" structure when it dimerizes. Members of the C/EBP family can form homodimers or heterodimers with other C/EBPs and with other transcription factors, which may or may not contain the leucine zipper domain. The dimerization is necessary to enable C/EBPs to bind specifically to DNA through a palindromic sequence in the major groove of the DNA. 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 other organs. C/EBP proteins are involved in different cellular responses, such as in the control of cellular proliferation, growth and differentiation, in metabolism, and in immunity. Nearly all the members of the C/EBP family can induce transcription through their activation domains by interacting with components of the basal transcription apparatus. (C/EBPγ is an exception that lacks a functional transcriptional activation domain.) Their expression is regulated at multiple levels, including through hormones, mitogens, cytokines, nutrients, and other factors.

This protein is expressed in the mammalian nervous system and plays a significant role in the development and function of nerve cells. C/EBPβ plays a role in neuronal differentiation, in learning, in memory processes, in glial and neuronal cell functions, and in neurotrophic factor expression.

Gene transcription

The C/EBPα, C/EBPβ, C/EBPγ and C/EBPδ genes are without introns. C/EBPζ has four exons; C/EBPε has two, which lead to four isoforms due to an alternative use of promoters and splicing. For C/EBPα and C/EBPβ, different sizes of polypeptides can be produced by alternative use of initiation codons. This is thought to be due to weak ribosome scanning mechanisms. The mRNA of C/EBPα can transcribe into two polypeptides. 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. LIP can act as an inhibitor of the other C/EBPs by forming non-functional heterodimers.

Regulation

C/EBPβ function is regulated by multiple mechanisms, including phosphorylation, acetylation, activation, autoregulation, and repression via other transcription factors, oncogenic elements, or chemokines. C/EBPβ can interact with CREB, NF-κB, and other proteins, 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.

It was shown in C. elegans that multiple cis elements of cebp-1 mRNA 3'UTR help in expression of CEBP-1 in neuronal development.^[4]

Clinical significance

Role in adipogenesis

C/EBPβ and δ are transiently induced during the early stages of adipocyte differentiation (adipogenesis), while C/EBPα is upregulated during the terminal stages of adipogenesis. In vitro and in vivo studies have demonstrated that each plays an important role in this process. For example, Murine Embryonic Fibroblasts (MEFs) from mice lacking both C/EBPβ and C/EBPδ show impaired adipocyte differentiation in response to adipogenic stimuli.^[5] In contrast, ectopic expression of C/EBPβ and δ in 3T3-L1 preadipocytes promotes adipogenesis, even in the absence of adipogenic stimuli.^[6][7] 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 both for adipogenesis and for normal adipocyte function. For example, mice lacking C/EBPα in all tissues except the liver (where it is needed to avoid postnatal lethality) show abnormal adipose tissue formation.^[8] Moreover, ectopic expression of C/EBPα in various fibroblast cell lines promotes adipogenesis.^[9] C/EBPα probably promotes adipogenesis by inducing the expression of PPARγ.^[10]

Role in osteoporosis

C/EBPβ has been found to have a role in the development of osteoporosis. The full-length isoform of the C/EBPβ protein (LAP) activates the MafB gene, whereas the short isoform (LIP) suppresses it. MafB gene activation suppresses the formation of osteoclasts. Thus, upregulation of LAP diminishes the number of osteoclasts, and this weakens the osteoporotic process, whereas upregulation of LIP does the opposite, increasing loss of bone mass.

The LAP/LIP balance is determined by the mTOR protein. Inhibition of the expression of mTOR can stop osteoclast activity.^[11]

References

1. 
   ^ Miller M, Shuman JD, Sebastian T, Dauter Z, Johnson PF (Apr 2003). "Structural basis for DNA recognition by the basic region leucine zipper transcription factor CCAAT/enhancer-binding protein alpha". The Journal of Biological Chemistry. 278 (17): 15178–84. doi:10.1074/jbc.M300417200. PMID 12578822..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output .citation q{quotes:"""""""'""'"}.mw-parser-output .citation .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .citation .cs1-lock-limited a,.mw-parser-output .citation .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .citation .cs1-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/4/4c/Wikisource-logo.svg/12px-Wikisource-logo.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output .cs1-maint{display:none;color:#33aa33;margin-left:0.3em}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
   


2. 
   ^ Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR (Sep 2003). "CCAAT/enhancer-binding protein family members recruit the coactivator CREB-binding protein and trigger its phosphorylation". The Journal of Biological Chemistry. 278 (38): 36959–65. doi:10.1074/jbc.M303147200. PMID 12857754.
   


3. 
   ^ Ramji DP, Foka P (Aug 2002). "CCAAT/enhancer-binding proteins: structure, function and regulation". The Biochemical Journal. 365 (Pt 3): 561–75. doi:10.1042/BJ20020508. PMC 1222736. PMID 12006103.
   


4. 
   ^ Sharifnia P, Kim KW, Wu Z, Jin Y (September 2017). "Distinct cis elements in the 3' UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development". Developmental Biology. 429 (1): 240–248. doi:10.1016/j.ydbio.2017.06.022. PMC 5828015. PMID 28673818.
   


5. 
   ^ Tanaka T, Yoshida N, Kishimoto T, Akira S (Dec 1997). "Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene". The EMBO Journal. 16 (24): 7432–43. doi:10.1093/emboj/16.24.7432. PMC 1170343. PMID 9405372.
   


6. 
   ^ Cao Z, Umek RM, McKnight SL (Sep 1991). "Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells". Genes & Development. 5 (9): 1538–52. doi:10.1101/gad.5.9.1538. PMID 1840554.
   


7. 
   ^ Yeh WC, Cao Z, Classon M, McKnight SL (Jan 1995). "Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins". Genes & Development. 9 (2): 168–81. doi:10.1101/gad.9.2.168. PMID 7531665.
   


8. 
   ^ Linhart HG, Ishimura-Oka K, DeMayo F, Kibe T, Repka D, Poindexter B, Bick RJ, Darlington GJ (Oct 2001). "C/EBPalpha is required for differentiation of white, but not brown, adipose tissue". Proceedings of the National Academy of Sciences of the United States of America. 98 (22): 12532–7. doi:10.1073/pnas.211416898. PMC 60088. PMID 11606718.
   


9. 
   ^ Freytag SO, Paielli DL, Gilbert JD (Jul 1994). "Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells". Genes & Development. 8 (14): 1654–63. doi:10.1101/gad.8.14.1654. PMID 7958846.
   


10. 
    ^ Clarke SL, Robinson CE, Gimble JM (Nov 1997). "CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter". Biochemical and Biophysical Research Communications. 240 (1): 99–103. doi:10.1006/bbrc.1997.7627. PMID 9367890.
    


11. 
    ^ [1], Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis
    

External links

• 
  CCAAT-Enhancer-Binding+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e Transcription factors and intracellular receptors
(1) Basic domains (1.1) Basic leucine zipper (bZIP) Activating transcription factor AATF 1 2 3 4 5 6 7 AP-1 c-Fos FOSB FOSL1 FOSL2 JDP2 c-Jun JUNB JunD BACH 1 2 BATF BLZF1 C/EBP α β γ δ ε ζ CREB 1 3 L1 CREM DBP DDIT3 GABPA GCN4 HLF MAF B F G K NFE 2 L1 L2 L3 NFIL3 NRL NRF 1 2 3 XBP1 (1.2) Basic helix-loop-helix (bHLH) ATOH1 AhR AHRR ARNT ASCL1 BHLH 2 3 9 ARNTL ARNTL ARNTL2 CLOCK EPAS1 FIGLA HAND 1 2 HES 5 6 HEY 1 2 L HES1 HIF 1A 3A ID 1 2 3 4 LYL1 MESP2 MXD4 MYCL1 MYCN Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 Neurogenins 1 2 3 NeuroD 1 2 NPAS 1 2 3 OLIG 1 2 Pho4 Scleraxis SIM 1 2 TAL 1 2 Twist USF1 (1.3) bHLH-ZIP AP-4 MAX MXD1 MXD3 MITF MNT MLX MLXIPL MXI1 Myc SREBP 1 2 (1.4) NF-1 NFI A B C X SMAD R-SMAD 1 2 3 5 9 I-SMAD 6 7 4) (1.5) RF-X RFX 1 2 3 4 5 6 ANK (1.6) Basic helix-span-helix (bHSH) AP-2 α β γ δ ε
(2) Zinc finger DNA-binding domains (2.1) Nuclear receptor (Cys4) .mw-parser-output .nobold{font-weight:normal} subfamily 1 Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR subfamily 2 COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX subfamily 3 Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ subfamily 4 NUR NGFIB NOR1 NURR1 subfamily 5 LRH-1 SF1 subfamily 6 GCNF subfamily 0 DAX1 SHP (2.2) Other Cys4 GATA 1 2 3 4 5 6 MTA 1 2 3 TRPS1 (2.3) Cys2His2 General transcription factors TFIIA TFIIB TFIID TFIIE 1 2 TFIIF 1 2 TFIIH 1 2 4 2I 3A 3C1 3C2 ATBF1 BCL 6 11A 11B CTCF E4F1 EGR 1 2 3 4 ERV3 GFI1 GLI-Krüppel family 1 2 3 REST S1 S2 YY1 HIC 1 2 HIVEP 1 2 3 IKZF 1 2 3 ILF 2 3 KLF 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 MTF1 MYT1 OSR1 PRDM9 SALL 1 2 3 4 SP 1 2 4 7 8 TSHZ3 WT1 Zbtb7 7A 7B ZBTB 11 16 17 20 32 33 40 zinc finger 3 7 9 10 19 22 24 33B 34 35 41 43 44 51 74 143 146 148 165 202 217 219 238 239 259 267 268 281 295 300 318 330 346 350 365 366 384 423 451 452 471 593 638 644 649 655 (2.4) Cys6 HIVEP1 (2.5) Alternating composition AIRE DIDO1 GRLF1 ING 1 2 4 JARID 1A 1B 1C 1D 2 JMJD1B (2.6) WRKY WRKY
(3) Helix-turn-helix domains (3.1) Homeodomain ARX CDX 1 2 CRX CUTL1 DBX 1 2 DLX 1 2 3 4 5 6 EMX 1 2 EN 1 2 FHL 1 2 3 HESX1 HHEX HLX Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 HOPX IRX 1 2 3 4 5 6 MKX LMX 1A 1B MEIS 1 2 MEOX2 MNX1 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 6-1 6-2 NOBOX PBX 1 2 3 PHF 1 3 6 8 10 16 17 20 21A PHOX 2A 2B PITX 1 2 3 POU domain PIT-1 BRN-3: A B C Octamer transcription factor: 1 2 3/4 6 7 11 OTX 1 2 PDX1 SATB2 SHOX2 SIX 1 2 3 4 5 VAX1 ZEB 1 2 (3.2) Paired box PAX 1 2 3 4 5 6 7 8 9 PRRX 1 2 RAX (3.3) Fork head / winged helix E2F 1 2 3 4 5 FOX proteins A1 A2 A3 C1 C2 D3 D4 E1 E3 F1 G1 H1 I1 J1 J2 K1 K2 L2 M1 N1 N3 O1 O3 O4 P1 P2 P3 P4 (3.4) Heat shock factors HSF 1 2 4 (3.5) Tryptophan clusters ELF 2 4 5 EGF ELK 1 3 4 ERF ETS 1 2 ERG SPIB ETV 1 4 5 6 FLI1 Interferon regulatory factors 1 2 3 4 5 6 7 8 MYB MYBL2 (3.6) TEA domain transcriptional enhancer factor 1 2 3 4
(4) β-Scaffold factors with minor groove contacts (4.1) Rel homology region NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5 (4.2) STAT STAT 1 2 3 4 5 6 (4.3) p53 p53 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF TP63 (4.4) MADS box Mef2 A B C D SRF (4.6) TATA-binding proteins TBP TBPL1 (4.7) High-mobility group BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B LEF1 SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 18 21 SRY SSRP1 TCF 3 4 TOX 1 2 3 4 (4.9) Grainyhead TFCP2 (4.10) Cold-shock domain CSDA YBX1 (4.11) Runt CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1
(0) Other transcription factors (0.2) HMGI(Y) HMGA 1 2 HBP1 (0.3) Pocket domain Rb RBL1 RBL2 (0.5) AP-2/EREBP-related factors Apetala 2 EREBP B3 (0.6) Miscellaneous ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma
see also transcription factor/coregulator deficiencies

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