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BIBTEX RIS

Biological Role of the CCAAT/Enhancer-binding Protein Family of Transcription Factors

1998; Elsevier BV; Volume: 273; Issue: 44 Linguagem: Inglês

10.1074/jbc.273.44.28545

ISSN

1083-351X

Autores

Julie Lekstrom-Himes, Kleanthis G. Xanthopoulos,

Tópico(s)

interferon and immune responses

Resumo

CCAAT/enhancer-binding proteins (C/EBPs) comprise a family of transcription factors that are critical for normal cellular differentiation and function in a variety of tissues. The prototypic C/EBP is a modular protein, consisting of an activation domain, a dimerization bZIP region, and a DNA-binding domain. All family members share the highly conserved dimerization domain, required for DNA binding, by which they form homo- and heterodimers with other family members. C/EBPs are least conserved in their activation domains and vary from strong activators to dominant negative repressors. The pleiotropic effects of C/EBPs are in part because of tissue- and stage-specific expression. Dimerization of different C/EBP proteins precisely modulates transcriptional activity of target genes. Recent work with mice deficient in specific C/EBPs underscores the effects of these factors in tissue development, function, and response to injury. CCAAT/enhancer-binding proteins (C/EBPs) comprise a family of transcription factors that are critical for normal cellular differentiation and function in a variety of tissues. The prototypic C/EBP is a modular protein, consisting of an activation domain, a dimerization bZIP region, and a DNA-binding domain. All family members share the highly conserved dimerization domain, required for DNA binding, by which they form homo- and heterodimers with other family members. C/EBPs are least conserved in their activation domains and vary from strong activators to dominant negative repressors. The pleiotropic effects of C/EBPs are in part because of tissue- and stage-specific expression. Dimerization of different C/EBP proteins precisely modulates transcriptional activity of target genes. Recent work with mice deficient in specific C/EBPs underscores the effects of these factors in tissue development, function, and response to injury. CCAAT/enhancer-binding protein lipopolysaccharide interleukin tumor necrosis factor granulocyte colony-stimulating factor granulocyte-macrophage colony-stimulating factor C/EBP homologous protein peroxisome proliferator-activated receptor. The CCAAT/enhancer-binding proteins (C/EBPs)1 encompass a family of transcription factors with structural as well as functional homologies. Similarities between C/EBP family members suggest an evolutionary history of genetic duplications with subsequent pressure to diversify. The resulting family of proteins varies in tissue specificity and transactivating ability. Since the cloning of the family's original member, C/EBPα, nearly a decade ago, five other C/EBPs have been identified that interact with each other and transcription factors in other protein families to regulate mRNA transcription. The pleiotropic effects of C/EBPs are in part because of tissue- and stage-specific expression, leaky ribosomal reading, post-transcriptional modifications, and variable DNA binding specificities. These mechanisms result in variable amounts of the C/EBP isoforms, available to dimerize and bind to cognate sites in different tissues. Recent work with mice genetically altered to abolish expression of C/EBPs underscores the role these factors play in normal tissue development and cellular function, cellular proliferation, and functional differentiation. The prototypic C/EBP, like many transcription factors, is a modular protein, consisting of an activation domain, a DNA-binding basic region, and a leucine-rich dimerization domain. The dimerization domain, aptly termed the “leucine zipper,” is a heptad of leucine repeats that intercalate with repeats of the dimer partner, forming a coiled coil of α-helices in parallel orientation (1Agre P. Johnson P.F. McKnight S.L. Science. 1989; 246: 922-926Crossref PubMed Scopus (157) Google Scholar, 2Vinson C.R. Hai T. Boyd S.M. Genes Dev. 1993; 7: 1047-1058Crossref PubMed Scopus (291) Google Scholar, 3Landschulz W.H. Johnson P.F. McKnight S.L. Science. 1988; 240: 1759-1764Crossref PubMed Scopus (2534) Google Scholar). Electrostatic interactions between amino acids along the dimerization interface determine the specificity of dimer formation among C/EBP family members as well as with transcription factors of the NF-κB and Fos/Jun families (2Vinson C.R. Hai T. Boyd S.M. Genes Dev. 1993; 7: 1047-1058Crossref PubMed Scopus (291) Google Scholar). C/EBP dimerization is a prerequisite to DNA binding (4Landschulz W.H. Johnson P.F. McKnight S.L. Science. 1989; 243: 1681-1688Crossref PubMed Scopus (425) Google Scholar). DNA binding specificity, however, is determined by the DNA contact surface, the “basic” region of approximately 20 amino acids, upstream of the leucine zipper, specifically by three amino acids lying along the protein-DNA interface (1Agre P. Johnson P.F. McKnight S.L. Science. 1989; 246: 922-926Crossref PubMed Scopus (157) Google Scholar, 5Johnson P.F. Mol. Cell. Biol. 1993; 13: 6919-6930Crossref PubMed Scopus (102) Google Scholar). Domains responsible for transcriptional activation and/or repression are located in the N-terminal end of the protein. In this review, C/EBP genes are designated C/EBPα, -β, -γ, -δ, -ε, and -ζ as proposed by Cao et al. (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar); however, Table I lists alternative nomenclature. C/EBPα was the first member cloned (7Landschulz W.H. Johnson P.F. Adashi E.Y. Graves B.J. McKnight S.L. Genes Dev. 1988; 2: 786-800Crossref PubMed Scopus (629) Google Scholar, 8Birkenmeier E.H. Gwynn B. Howard S. Jerry J. Gordon J.I. Landschulz W.H. McKnight S.L. Genes Dev. 1989; 3: 1146-1156Crossref PubMed Scopus (463) Google Scholar, 9Christy R.J. Kaestner K.H. Geiman D.E. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 2593-2597Crossref PubMed Scopus (329) Google Scholar, 10Hendricks-Taylor L.R. Bachinski L.L. Siciliano M.J. Fertitta A. Trask B. DeJong P.J. Ledbetter D.H. Darlington G.J. Genomics. 1992; 14: 12-17Crossref PubMed Scopus (42) Google Scholar, 11Xanthopoulos K.G. Mirkovitch J. Friedman J.M. Darnell Jr., J.E. Cytogenet. Cell Genet. 1989; 50: 174-175Crossref PubMed Google Scholar, 12Antonson P. Xanthopoulos K.G. Biochem. Biophys. Res. Commun. 1995; 215: 106-113Crossref PubMed Scopus (81) Google Scholar). Expression patterns of C/EBPα mRNA are similar in the mouse and human with measurable levels in liver, adipose, intestine, lung, adrenal gland, peripheral blood mononuclear cells, and placenta (8Birkenmeier E.H. Gwynn B. Howard S. Jerry J. Gordon J.I. Landschulz W.H. McKnight S.L. Genes Dev. 1989; 3: 1146-1156Crossref PubMed Scopus (463) Google Scholar,12Antonson P. Xanthopoulos K.G. Biochem. Biophys. Res. Commun. 1995; 215: 106-113Crossref PubMed Scopus (81) Google Scholar). In liver and adipose, highest levels of C/EBPα mRNA are detected only in differentiated tissue (8Birkenmeier E.H. Gwynn B. Howard S. Jerry J. Gordon J.I. Landschulz W.H. McKnight S.L. Genes Dev. 1989; 3: 1146-1156Crossref PubMed Scopus (463) Google Scholar, 12Antonson P. Xanthopoulos K.G. Biochem. Biophys. Res. Commun. 1995; 215: 106-113Crossref PubMed Scopus (81) Google Scholar). Autoregulation of C/EBPα mRNA occurs by different mechanisms in the mouse and in humans. The murine C/EBPα promoter directly binds C/EBPα within 200 base pairs of the transcriptional start resulting in 3-fold activation (9Christy R.J. Kaestner K.H. Geiman D.E. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 2593-2597Crossref PubMed Scopus (329) Google Scholar). Autoregulation of the human C/EBPα promoter occurs by C/EBPα-induced binding of USF, a ubiquitously expressed transcription factor, to its upstream site within the C/EBPα promoter (13Timchenko N. Wilson D.R. Taylor L.R. Abdelsayed S. Wilde M. Sawadogo M. Darlington G.J. Mol. Cell. Biol. 1995; 15: 1192-1202Crossref PubMed Google Scholar).Table ICloned C/EBP genes and phenotypic characterization of knockout modelsNameAlternative nameExpression patternKnockout modelPhenotypic abnormalitiesHepaticMetabolicHematologicOtherC/EBPαC/EBPLiver, adipose, intestine, lung, adrenal gland, placenta, ovary, PBMC1-aPeripheral blood mononuclear cells.YesHepatocyte proliferation, perinatal lethalDefective lipid storage, defective carbohydrate metabolismMyeloid maturation block at myeloblast stageC/EBPβNF-IL6, IL-6DBP LAP, CRP2 AGP/EBP, NF-M ApC/EBPLiver, intestine, lung, adiposeYesNone detectedDefective carbohydrate metabolism, defective lipid storage (synergistic with C/EBPδ)Immunodeficient, defective Th1 response, Macrophage phagosome defectFemale sterilityC/EBPγIg/EBPUbiquitousNoC/EBPδCELFLiver, lung,YesNone detectedDefective lipidNone detectedNeurologicCRP3 adipose, storage defectsNF-IL6b intestine (synergisticRcC/EBP2 with C/EBPβ)C/EBPɛCRP1Myeloid and lymphoid lineagesYesNone detectedNone detectedImmunodeficient, granulocyte defects, myeloid proliferationC/EBPζCHOPUbiquitousYes, inGadd 153 progress1-a Peripheral blood mononuclear cells. Open table in a new tab Two isoforms of C/EBPα are generated from its mRNA by a ribosomal scanning mechanism (14Lin F. MacDougald O.A. Diehl A.M. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9606-9610Crossref PubMed Scopus (259) Google Scholar, 15Ossipow V. Descombes P. Schibler U. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8219-8223Crossref PubMed Scopus (322) Google Scholar). The full-length protein is 42 kDa and contains three transactivation domains (TEI–III) (16Nerlov C. Ziff E.B. Genes Dev. 1994; 8: 350-362Crossref PubMed Scopus (118) Google Scholar, 17Nerlov C. Ziff E.B. EMBO J. 1995; 14: 4318-4328Crossref PubMed Scopus (134) Google Scholar, 18Friedman A.D. McKnight S.L. Genes Dev. 1990; 4: 1416-1426Crossref PubMed Scopus (127) Google Scholar). TEI and TEII mediate cooperative binding of C/EBPα to TBP (TATA box-binding protein) and TFIIB, two components of the RNA polymerase II basal transcriptional apparatus (17Nerlov C. Ziff E.B. EMBO J. 1995; 14: 4318-4328Crossref PubMed Scopus (134) Google Scholar). TEIII contains a negative regulatory subdomain (16Nerlov C. Ziff E.B. Genes Dev. 1994; 8: 350-362Crossref PubMed Scopus (118) Google Scholar). A fraction of ribosomes ignore the first two AUG codons and initiate translation at the third AUG, 351 nucleotides downstream of the first AUG (14Lin F. MacDougald O.A. Diehl A.M. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9606-9610Crossref PubMed Scopus (259) Google Scholar, 15Ossipow V. Descombes P. Schibler U. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8219-8223Crossref PubMed Scopus (322) Google Scholar). This shorter 30-kDa protein retains its dimerization and DNA-binding domains; however, it possesses an altered transactivation potential compared with the 42-kDa isoform (14Lin F. MacDougald O.A. Diehl A.M. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 9606-9610Crossref PubMed Scopus (259) Google Scholar, 15Ossipow V. Descombes P. Schibler U. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8219-8223Crossref PubMed Scopus (322) Google Scholar). The human, mouse, and rat genes for C/EBPβ have been cloned (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar, 19Thomassin H. Hamel D. Bernier D. Guertin M. Belanger L. Nucleic Acids Res. 1992; 20: 3091-3098Crossref PubMed Scopus (68) Google Scholar, 20Akira S. Isshiki H. Sugita T. Tanabe O. Kinoshita S. Nishio Y. Nakajima T. Hirano T. Kishimoto T. EMBO J. 1990; 9: 1897-1906Crossref PubMed Scopus (1211) Google Scholar, 21Descombes P. Chijkier M. Lichtsteiner S. Falvey E. Schibler U. Genes Dev. 1990; 4: 1541-1551Crossref PubMed Scopus (420) Google Scholar, 22Poli V. Mancini F.P. Cortese R. Cell. 1990; 63: 643-653Abstract Full Text PDF PubMed Scopus (459) Google Scholar, 23Chang C.J. Chen T.T. Lei H.Y. Chen D.S. Lee S.C. Mol. Cell. Biol. 1990; 10: 6642-6653Crossref PubMed Scopus (200) Google Scholar). Constitutive expression of C/EBPβ is highest in liver, intestine, lung, and adipose; however, in the mouse, it is also detectable in kidney, heart, and spleen by Northern analysis (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar). Stimulation with lipopolysaccharide (LPS), IL-6, IL-1, dexamethasone, and glucagon strongly induces C/EBPβ expression, suggesting a role in the mediation of the inflammatory response (20Akira S. Isshiki H. Sugita T. Tanabe O. Kinoshita S. Nishio Y. Nakajima T. Hirano T. Kishimoto T. EMBO J. 1990; 9: 1897-1906Crossref PubMed Scopus (1211) Google Scholar, 24An M.R. Hsieh C.-C. Reisner P.D. Rabek J.P. Scott S.G. Kuninger D.T. Papconstantinou J. Mol. Cell. Biol. 1996; 16: 2295-2306Crossref PubMed Google Scholar, 25Alam T. An M.R. Papaconstantinou J. J. Biol. Chem. 1992; 267: 5021-5024Abstract Full Text PDF PubMed Google Scholar, 26Matsuno F. Chowdhury S. Gotoh T. Iwase K. Matsuzaki H. Takatsuki K. Mori M. Takiguchi M. J. Biochem. (Tokyo). 1996; 119: 524-532Crossref PubMed Scopus (60) Google Scholar). Like C/EBPα, two C/EBPβ isoforms are generated from a single mRNA by a leaky ribosomal scanning mechanism. The full-length 32-kDa protein, also termed LAP, encodes for the conserved activation domains found in other C/EBP proteins, as well as two regulatory domains, RD1 and RD2, which confer DNA binding inhibition in a cell type-specific manner (27Williams S.C. Baer M. Dillner A.J. Johnson P.F. EMBO J. 1995; 14: 3170-3183Crossref PubMed Scopus (200) Google Scholar). The truncated protein, LIP, translated from the third, in-frame AUG, possesses only the DNA-binding and leucine zipper domains (22Poli V. Mancini F.P. Cortese R. Cell. 1990; 63: 643-653Abstract Full Text PDF PubMed Scopus (459) Google Scholar, 28Descombes P. Schebler U. Cell. 1991; 67: 569-579Abstract Full Text PDF PubMed Scopus (860) Google Scholar). Heterodimerization of the truncated isoform with the full-length C/EBPβ (LAP) attenuates transcriptional activity in substoichiometric amounts, suggesting a dominant negative mechanism of transcriptional regulation (28Descombes P. Schebler U. Cell. 1991; 67: 569-579Abstract Full Text PDF PubMed Scopus (860) Google Scholar). C/EBPβ was originally identified as a mediator of IL-6 signaling, binding to IL-6-responsive elements in the promoters of acute phase response genes TNF, IL-8, and G-CSF (20Akira S. Isshiki H. Sugita T. Tanabe O. Kinoshita S. Nishio Y. Nakajima T. Hirano T. Kishimoto T. EMBO J. 1990; 9: 1897-1906Crossref PubMed Scopus (1211) Google Scholar, 22Poli V. Mancini F.P. Cortese R. Cell. 1990; 63: 643-653Abstract Full Text PDF PubMed Scopus (459) Google Scholar). Signal transduction of the acute phase response by IL-1 and LPS also induces C/EBPβ transcription (20Akira S. Isshiki H. Sugita T. Tanabe O. Kinoshita S. Nishio Y. Nakajima T. Hirano T. Kishimoto T. EMBO J. 1990; 9: 1897-1906Crossref PubMed Scopus (1211) Google Scholar, 25Alam T. An M.R. Papaconstantinou J. J. Biol. Chem. 1992; 267: 5021-5024Abstract Full Text PDF PubMed Google Scholar). TNFα promotes nuclear localization of C/EBPβ and C/EBPδ in response to inflammatory stress (29Yin M. Yang S.Q. Lin H.G. Lane M.D. Chatterjee S. Diehl A.M. J. Biol. Chem. 1996; 271: 17974-17978Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Cytokine stimulation further increases C/EBPβ transcriptional activity by enhanced DNA binding (22Poli V. Mancini F.P. Cortese R. Cell. 1990; 63: 643-653Abstract Full Text PDF PubMed Scopus (459) Google Scholar). Post-transcriptional modifications of C/EBPβ by protein kinases in the signal transduction pathway of C/EBPβ appear to activate transcription (30Nakajima T. Kinoshita S. Sasagawa T. Sasaki K. Naruto M. Kishimoto T. Akira S. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 2207-2211Crossref PubMed Scopus (516) Google Scholar, 31Trautwein C. Caelles C. van der Geer P. Hunter T. Karin M. Chojkier M. Nature. 1993; 364: 544-547Crossref PubMed Scopus (293) Google Scholar). C/EBPγ is a short, intronless gene, whose mRNA is ubiquitously expressed with highest levels found in non-differentiated, progenitor cells (19Thomassin H. Hamel D. Bernier D. Guertin M. Belanger L. Nucleic Acids Res. 1992; 20: 3091-3098Crossref PubMed Scopus (68) Google Scholar, 32Roman C. Platero J.S. Shuman J. Calame K. Genes Dev. 1990; 4: 1404-1415Crossref PubMed Scopus (191) Google Scholar, 33Cooper C. Henderson A. Artandi S. Avitahl N. Calame K. Nucleic Acids Res. 1995; 23: 4371-4377Crossref PubMed Scopus (111) Google Scholar). The 16.4-kDa encoded protein possesses a leucine zipper dimerization domain and DNA-binding region; however, it lacks transcriptional transactivating elements (33Cooper C. Henderson A. Artandi S. Avitahl N. Calame K. Nucleic Acids Res. 1995; 23: 4371-4377Crossref PubMed Scopus (111) Google Scholar). Heterodimerization with C/EBPα and C/EBPβ attenuates transcriptional activation of target genes, suggesting dominant negative regulation of C/EBP transactivation in undifferentiated, non-induced cells (33Cooper C. Henderson A. Artandi S. Avitahl N. Calame K. Nucleic Acids Res. 1995; 23: 4371-4377Crossref PubMed Scopus (111) Google Scholar). C/EBPδ is an intronless gene (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar, 34Jenkins N.A. Gilbert D.J. Cho B.C. Strobel M.C. Williams S.C. Copeland N.G. Johnson P.F. Genomics. 1995; 28: 333-336Crossref PubMed Scopus (27) Google Scholar, 35Cleutjens C.B. Van Eekelen C.C. van Dekken H. Smit E.M. Hagemeijer A. Wagner M.J. Wells D.E. Trapman J. Genomics. 1993; 16: 520-523Crossref PubMed Scopus (28) Google Scholar, 36Kinoshita S. Akira S. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 1473-1476Crossref PubMed Scopus (258) Google Scholar, 37Kageyama R. Sasai Y. Nakanishi S. J. Biol. Chem. 1991; 23: 15525-15531Abstract Full Text PDF Google Scholar, 38Williams S.C. Cantwell C.A. Johnson P.F. Genes Dev. 1991; 5: 1553-1567Crossref PubMed Scopus (439) Google Scholar). Constitutive expression of C/EBPδ is detected in intestines, adipose, and lung, with high levels of expression in all tissues following LPS stimulation (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar, 25Alam T. An M.R. Papaconstantinou J. J. Biol. Chem. 1992; 267: 5021-5024Abstract Full Text PDF PubMed Google Scholar, 36Kinoshita S. Akira S. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 1473-1476Crossref PubMed Scopus (258) Google Scholar). The 269-amino acid protein encodes a leucine zipper dimerization domain and DNA-binding region, readily forming heterodimers with C/EBPα and C/EBPβ (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar). Transactivating efficiency of C/EBPδ is comparable with that of C/EBPα and C/EBPβ (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar). The DNA-binding region of C/EBPδ differs from C/EBPα in that it contains 2 proline and 4 glycine residues, which may interrupt the predicted α-helical structure (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar). Diminished DNA binding affinity of the C/EBPδ basic domain compared with C/EBPα and C/EBPβ is likely the result of sequence divergence (6Cao Z. Umek R.M. McKnight S.L. Genes Dev. 1991; 5: 1538-1552Crossref PubMed Scopus (1342) Google Scholar). C/EBPε was originally identified from a rat genomic library, but the start site could not be determined and no expression was detected (38Williams S.C. Cantwell C.A. Johnson P.F. Genes Dev. 1991; 5: 1553-1567Crossref PubMed Scopus (439) Google Scholar). Subsequently, the full-length C/EBPε gene was cloned (39Antonson P. Stellan B. Yamanaka R. Xanthopoulos K.G. Genomics. 1996; 35: 30-38Crossref PubMed Scopus (90) Google Scholar, 40Chumakov A.M. Grillier I. Chumakova E. Chih D. Slater J. Koeffler H.P. Mol. Cell. Biol. 1997; 17: 1375-1386Crossref PubMed Google Scholar). Human C/EBPε contains two intronic sequences and five in-frame AUG initiation sites, three of which satisfy the Kozak context (41Yamanaka R. Kim G-d. Radomska H.S. Lekstrom-Himes J. Smith L.T. Antonson P. Tenens D.G. Xanthopoulos K.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6462-6467Crossref PubMed Scopus (151) Google Scholar). Four mRNA isoforms, expressed primarily in myeloid and lymphoid cells, are generated by the use of alternative promoters combined with differential splicing (41Yamanaka R. Kim G-d. Radomska H.S. Lekstrom-Himes J. Smith L.T. Antonson P. Tenens D.G. Xanthopoulos K.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6462-6467Crossref PubMed Scopus (151) Google Scholar). The highest level of expression is detected in promyelocyte and late myeloblast-like cell lines (39Antonson P. Stellan B. Yamanaka R. Xanthopoulos K.G. Genomics. 1996; 35: 30-38Crossref PubMed Scopus (90) Google Scholar, 42Morosetti R. Park D.J. Chumakov A.M. Grillier I. Shiohara M. Gombart A.F. Nakamaki T. Weinberg K. Koeffler H.P. Blood. 1997; 90: 2591-2600Crossref PubMed Google Scholar). Further, induction of C/EBPε mRNA with retinoids promotes granulocytic differentiation of promyelocyte line NB4 (42Morosetti R. Park D.J. Chumakov A.M. Grillier I. Shiohara M. Gombart A.F. Nakamaki T. Weinberg K. Koeffler H.P. Blood. 1997; 90: 2591-2600Crossref PubMed Google Scholar, 43Chih D.Y. Chumakov A.M. Park D.J. Silla A.G. Koeffler H.P. Blood. 1997; 90: 2987-2994Crossref PubMed Google Scholar). The four C/EBPε mRNA isoforms translate into three proteins possessing identical leucine zipper domains and variably truncated activation domains, with differing transcriptional activities (40Chumakov A.M. Grillier I. Chumakova E. Chih D. Slater J. Koeffler H.P. Mol. Cell. Biol. 1997; 17: 1375-1386Crossref PubMed Google Scholar, 41Yamanaka R. Kim G-d. Radomska H.S. Lekstrom-Himes J. Smith L.T. Antonson P. Tenens D.G. Xanthopoulos K.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6462-6467Crossref PubMed Scopus (151) Google Scholar). C/EBPζ, which is induced by DNA damage, was originally cloned in hamster and named growth arrest and DNA damage-inducible gene (gadd153) (44Fornace A.J. Nebert D.W. Hollander M.C. Luethy J.D. Papathanasiou M. Fargnoli J. Holbrook N.J. Mol. Cell. Biol. 1989; 9: 4196-4203Crossref PubMed Scopus (647) Google Scholar). Spanning 5 kilobases, it consists of four exons and is expressed ubiquitously (45Ron D. Habener J.H. Genes Dev. 1992; 6: 439-453Crossref PubMed Scopus (979) Google Scholar). Like other C/EBP proteins, C/EBPζ possesses a leucine zipper dimerization domain and DNA-binding region (45Ron D. Habener J.H. Genes Dev. 1992; 6: 439-453Crossref PubMed Scopus (979) Google Scholar). C/EBPζ readily heterodimerizes with other C/EBPs; however, the presence of two prolines in the DNA-binding region disrupts its helical structure and prevents dimer binding to the cognate DNA enhancer element (45Ron D. Habener J.H. Genes Dev. 1992; 6: 439-453Crossref PubMed Scopus (979) Google Scholar). C/EBPζ functions as a dominant negative inhibitor of C/EBP transcriptional activation by preventing heterodimer binding of C/EBPα and C/EBPβ to classic C/EBP enhancer sequences (45Ron D. Habener J.H. Genes Dev. 1992; 6: 439-453Crossref PubMed Scopus (979) Google Scholar). Coordinate expression of specific C/EBP isoforms is essential for normal hepatic synthetic activity and response to injury; however, C/EBPα is the predominant nuclear signal regulating terminal hepatocyte differentiation and function. Elimination of C/EBPα in targeted mouse knockout models results in profound derangement of liver structure and function (Table I). C/EBPα −/− mice have disturbed hepatic architecture with acinar formation, resembling proliferative or pseudoglandular hepatocellular carcinoma (46Flodby P. Barlow C. Kylefjord H. Ahrlund-Richter L. Xanthopoulos K.G. J. Biol. Chem. 1996; 271: 24753-24760Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 47Wang N. Finegold M.J. Bradley A. Ou C.N. Abdelsayed S.V. Wilde M.D. Taylor L.R. Wilson D.R. Darlington G.J. Science. 1995; 269: 1108-1112Crossref PubMed Scopus (835) Google Scholar). c-Myc and c-Jun RNAs are induced consistent with a proliferative liver (46Flodby P. Barlow C. Kylefjord H. Ahrlund-Richter L. Xanthopoulos K.G. J. Biol. Chem. 1996; 271: 24753-24760Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). Metabolic derangements are pronounced with an impairment of hepatic glycogen storage, and the majority of mice die soon after birth because of hypoglycemia (46Flodby P. Barlow C. Kylefjord H. Ahrlund-Richter L. Xanthopoulos K.G. J. Biol. Chem. 1996; 271: 24753-24760Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 47Wang N. Finegold M.J. Bradley A. Ou C.N. Abdelsayed S.V. Wilde M.D. Taylor L.R. Wilson D.R. Darlington G.J. Science. 1995; 269: 1108-1112Crossref PubMed Scopus (835) Google Scholar). Known target genes of C/EBPα have decreased expression at birth, including albumin, glycogen synthase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase (47Wang N. Finegold M.J. Bradley A. Ou C.N. Abdelsayed S.V. Wilde M.D. Taylor L.R. Wilson D.R. Darlington G.J. Science. 1995; 269: 1108-1112Crossref PubMed Scopus (835) Google Scholar). Low level expression of phosphoenolpyruvate carboxykinase and perinatal lethality is also seen in a subset of C/EBPβ −/− mice, suggesting involvement of the C/EBPβ isoform in gluconeogenic pathways (48Croniger C. Trus M. Lysek-Stupp K. Cohen H. Liu Y. Darlington G.J. Poli V. Hanson R.W. Reshef L. J. Biol. Chem. 1997; 272: 26306-26312Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Hepatocyte proliferation following partial hepatectomy is accompanied by profound changes in C/EBP expression patterns. C/EBPα mRNA decreases following partial hepatectomy whereas C/EBPδ mRNA increases (49Mischoulon D. Rani B. Bucher N.L.R. Farmer S.R. Mol. Cell. Biol. 1992; 12: 2553-2560Crossref PubMed Google Scholar, 50Flodby P. Antonson P. Barlow C. Blanck A. Porsch-Hallstrom I. Xanthopoulos K.G. Exp. Cell Res. 1993; 208: 248-256Crossref PubMed Scopus (71) Google Scholar, 51Michalopoulos G.K. DeFrances M.C. Science. 1997; 276: 60-66Crossref PubMed Scopus (2884) Google Scholar). 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