Genomes and Genes
ccaat enhancer binding protein alpha
Summary: A CCAAT-enhancer-binding protein found in LIVER; ADIPOSE TISSUE; INTESTINES; LUNG; ADRENAL GLANDS; PLACENTA; OVARY and peripheral blood mononuclear cells (LEUKOCYTES, MONONUCLEAR). Experiments with knock-out mice have demonstrated that CCAAT-enhancer binding protein-alpha is essential for the functioning and differentiation of HEPATOCYTES and ADIPOCYTES.
- Zuo Y, Qiang L, Farmer S. Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma-associated repression of HDAC1 at the C/ebp alpha gene promoter. J Biol Chem. 2006;281:7960-7 pubmed
- Wang G, Timchenko N. Dephosphorylated C/EBPalpha accelerates cell proliferation through sequestering retinoblastoma protein. Mol Cell Biol. 2005;25:1325-38 pubmed..Our data demonstrate a new pathway by which the phosphorylation-dependent switch of biological functions of C/EBPalpha promotes liver proliferation. ..
- Laiosa C, Stadtfeld M, Xie H, de Andres Aguayo L, Graf T. Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity. 2006;25:731-44 pubmed..1 in multilineage precursors. ..
- CESENA T, Cardinaux J, Kwok R, Schwartz J. CCAAT/enhancer-binding protein (C/EBP) beta is acetylated at multiple lysines: acetylation of C/EBPbeta at lysine 39 modulates its ability to activate transcription. J Biol Chem. 2007;282:956-67 pubmed..These data suggest that acetylation of Lys-39 of C/EBPbeta, alone or in combination with acetylation at other lysines, may play a role in C/EBPbeta-mediated transcriptional activation. ..
- Meyer F, Perez S, Geiser V, Sintek M, Inman M, Jones C. A protein encoded by the bovine herpesvirus 1 latency-related gene interacts with specific cellular regulatory proteins, including CCAAT enhancer binding protein alpha. J Virol. 2007;81:59-67 pubmed..LR fusion protein interacts with two proteins that can induce apoptosis (Bid and Cdc42) and with CCAAT enhancer binding protein alpha (C/EBP-alpha)...
- Bennett K, Hackanson B, Smith L, Morrison C, Lang J, Schuller D, et al. Tumor suppressor activity of CCAAT/enhancer binding protein alpha is epigenetically down-regulated in head and neck squamous cell carcinoma. Cancer Res. 2007;67:4657-64 pubmedTumor suppressor CCAAT enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in cell cycle control and cellular differentiation...
- Schuster M, Porse B. C/EBPalpha: a tumour suppressor in multiple tissues?. Biochim Biophys Acta. 2006;1766:88-103 pubmed..Here, we will review these data and probe the possibility that C/EBPalpha also act as a tumour suppressor in other C/EBPalpha-expressing tissues. ..
- Lin L, Chen C, Lin D, Tsay W, Tang J, Yeh Y, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res. 2005;11:1372-9 pubmed
- Helbling D, Mueller B, Timchenko N, Schardt J, Eyer M, Betts D, et al. CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood. 2005;106:1369-75 pubmed..Inhibition of calreticulin by siRNA restored CEBPA levels. Our results suggest that modulation of CEBPA by calreticulin represents a novel mechanism involved in the differentiation block in CBFB-SMMHC AML. ..
- Gery S, Tanosaki S, Bose S, Bose N, Vadgama J, Koeffler H. Down-regulation and growth inhibitory role of C/EBPalpha in breast cancer. Clin Cancer Res. 2005;11:3184-90 pubmed..These results suggest that reduced expression of C/EBPalpha may play a role in the development and/or progression of breast cancer. ..
- Kirstetter P, Schuster M, Bereshchenko O, Moore S, Dvinge H, Kurz E, et al. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008;13:299-310 pubmed publisher..Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML. ..
- Liao H, Hyman M, Lawrence D, Pinsky D. Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1alpha, and C/EBPalpha. FASEB J. 2007;21:935-49 pubmed..These studies are relevant to ischemic up-regulation of the PAI-1 gene and consequent accrual of microvascular thrombus under ischemic conditions. ..
- Fox K, Fankell D, Erickson P, Majka S, Crossno J, Klemm D. Depletion of cAMP-response element-binding protein/ATF1 inhibits adipogenic conversion of 3T3-L1 cells ectopically expressing CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBP beta, or PPAR gamma 2. J Biol Chem. 2006;281:40341-53 pubmed..The data also indicate that CREB not only functions during the initiation of adipogenic conversion but also at later stages. ..
- Tang Q, Zhang J, Daniel Lane M. Sequential gene promoter interactions of C/EBPbeta, C/EBPalpha, and PPARgamma during adipogenesis. Biochem Biophys Res Commun. 2004;319:235-9 pubmed..g., 422/aP2) in the terminally differentiated state. Together these findings provide compelling evidence that C/EBPbeta, C/EBPalpha, and PPARgamma participate in a cascade during adipogenesis. ..
- Chattopadhyay S, Gong E, Hwang M, Park E, Lee H, Hong C, et al. The CCAAT enhancer-binding protein-alpha negatively regulates the transactivation of androgen receptor in prostate cancer cells. Mol Endocrinol. 2006;20:984-95 pubmed..Our results suggest C/EBPalpha as a potent AR corepressor and provide insight into the role of C/EBPalpha in prostate development and cancer. ..
- Wagner K, Zhang P, Rosenbauer F, Drescher B, Kobayashi S, Radomska H, et al. Absence of the transcription factor CCAAT enhancer binding protein alpha results in loss of myeloid identity in bcr/abl-induced malignancy. Proc Natl Acad Sci U S A. 2006;103:6338-43 pubmedThe lineage-determining transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is required for myeloid differentiation. Decreased function or expression of C/EBPalpha is often found in human acute myeloid leukemia...
- Wang D, D Costa J, Civin C, Friedman A. C/EBPalpha directs monocytic commitment of primary myeloid progenitors. Blood. 2006;108:1223-9 pubmed..A C/EBPalpha variant incapable of zippering with c-Jun did not induce monopoiesis, and a variant unable to bind NF-kappaB p50 stimulated granulopoiesis, suggesting their cooperation with C/EBPalpha during monocytic commitment...
- Jongen Lavrencic M, Sun S, Dijkstra M, Valk P, Lowenberg B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood. 2008;111:5078-85 pubmed publisher..MicroRNA expression apparently bears specific relationships to the heterogeneous pathobiology of AML. Distinctive microRNA signatures appear of potential value in the clinical diagnosis of AML. ..
- Choi S, Cho Y, Kim H, Park J. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun. 2007;356:312-7 pubmed..These results suggest that ROS repress the hepcidin gene by preventing C/EBPalpha and STAT-3 binding to hepcidin promoter during hypoxia. ..
- Khanna Gupta A. Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBP alpha). Blood Cells Mol Dis. 2008;41:77-81 pubmed publisherb>CCAAT enhancer binding protein alpha (C/EBP alpha) is the founding member of a family of basic region/leucine zipper (bZIP) transcription factors and is a master regulator of granulopoiesis...
- Rosen E. The transcriptional basis of adipocyte development. Prostaglandins Leukot Essent Fatty Acids. 2005;73:31-4 pubmed..These approaches will be discussed, along with the roles of some new transcriptional players in adipogenesis, including the O/E family of proteins. ..
- Takai N, Kawamata N, Walsh C, Gery S, Desmond J, Whittaker S, et al. Discovery of epigenetically masked tumor suppressor genes in endometrial cancer. Mol Cancer Res. 2005;3:261-9 pubmed..Our data suggest that C/ebpalpha and Tig1 function as tumor suppressor proteins in endometrial cancers and that their reexpression may be a therapeutic target. ..
- Bararia D, Trivedi A, Zada A, Greif P, Mulaw M, Christopeit M, et al. Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBPalpha. Leukemia. 2008;22:800-7 pubmed publisher..These findings point to a functional synergism between C/EBPalpha and HTATIP in myeloid differentiation and suggest that HTATIP might be an important player in leukemogenesis. ..
- Loomis K, Zhu S, Yoon K, Johnson P, Smart R. Genetic ablation of CCAAT/enhancer binding protein alpha in epidermis reveals its role in suppression of epithelial tumorigenesis. Cancer Res. 2007;67:6768-76 pubmed..Our study shows that C/EBPalpha is dispensable for epidermal homeostasis and provides genetic evidence that C/EBPalpha is a suppressor of epithelial tumorigenesis. ..
- Zhang P, Iwasaki Arai J, Iwasaki H, Fenyus M, Dayaram T, Owens B, et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity. 2004;21:853-63 pubmed..Therefore, C/EBP alpha is not only essential for granulocyte development but, in addition, is a regulator of hematopoietic stem cell activity. ..
- CESENA T, Cui T, Subramanian L, Fulton C, INIGUEZ LLUHI J, Kwok R, et al. Acetylation and deacetylation regulate CCAAT/enhancer binding protein beta at K39 in mediating gene transcription. Mol Cell Endocrinol. 2008;289:94-101 pubmed publisher..These findings suggest that acetylation of C/EBPbeta at K39 is an important and dynamic regulatory event that contributes to its ability to transactivate target genes, including those associated with adipogenesis and adipocyte function. ..
- Koschmieder S, Halmos B, Levantini E, Tenen D. Dysregulation of the C/EBPalpha differentiation pathway in human cancer. J Clin Oncol. 2009;27:619-28 pubmed publisher..The differentiation-inducing transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) is required for proper control of adipogenesis, glucose metabolism, granulocytic ..
- Paz Priel I, Cai D, Wang D, Kowalski J, Blackford A, Liu H, et al. CCAAT/enhancer binding protein alpha (C/EBPalpha) and C/EBPalpha myeloid oncoproteins induce bcl-2 via interaction of their basic regions with nuclear factor-kappaB p50. Mol Cancer Res. 2005;3:585-96 pubmed..Targeting interaction between C/EBPalpha basic region and NF-kappaB p50 may contribute to the therapy of AML and other malignancies expressing C/EBPs. ..
- Reddy S, Pakala S, Ohshiro K, Rayala S, Kumar R. MicroRNA-661, a c/EBPalpha target, inhibits metastatic tumor antigen 1 and regulates its functions. Cancer Res. 2009;69:5639-42 pubmed publisher..Based on these findings, we suggest that miR-661 be further investigated for therapeutic use in down-regulating the expression of MTA1 in cancer cells. ..
- Arinobu Y, Iwasaki H, Gurish M, Mizuno S, Shigematsu H, Ozawa H, et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci U S A. 2005;102:18105-10 pubmed..Thus, circulating basophils and tissue mast cells share a common developmental stage at which their fate decision might be controlled principally by C/EBPalpha. ..
- Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis M, Nervi C, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005;123:819-31 pubmed..Altogether, our data indicate that miR-223 plays a crucial role during granulopoiesis and point to the NFI-A repression as an important molecular pathway mediating gene reprogramming in this cell lineage. ..
- Roth M, Johnson P, Borger P, Bihl M, Rüdiger J, King G, et al. Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004;351:560-74 pubmed
- Bassères D, Levantini E, Ji H, Monti S, Elf S, Dayaram T, et al. Respiratory failure due to differentiation arrest and expansion of alveolar cells following lung-specific loss of the transcription factor C/EBPalpha in mice. Mol Cell Biol. 2006;26:1109-23 pubmedThe leucine zipper family transcription factor CCAAT enhancer binding protein alpha (C/EBPalpha) inhibits proliferation and promotes differentiation in various cell types...
- Harrison Findik D, Schafer D, Klein E, Timchenko N, Kulaksiz H, Clemens D, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem. 2006;281:22974-82 pubmed..Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBPalpha, which in turn leads to increased duodenal iron transport. ..
- Park M, Lee M, Choi J, Cho H, Choi Y, Yang U, et al. Phosphorylation of the large subunit of replication factor C is associated with adipocyte differentiation. FEBS J. 2007;274:1235-45 pubmed
- Koschmieder S, D Alo F, Radomska H, Schöneich C, Chang J, Konopleva M, et al. CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha. Blood. 2007;110:3695-705 pubmed..Because AML is characterized by arrested differentiation, our data suggest the inclusion of CDDO in the therapy of AML characterized by dysfunctional CEBPA expression. ..
- Liu H, Keefer J, Wang Q, Friedman A. Reciprocal effects of C/EBPalpha and PKCdelta on JunB expression and monocytic differentiation depend upon the C/EBPalpha basic region. Blood. 2003;101:3885-92 pubmed..Exogenous JunB restored AP-1 DNA-binding but did not prevent inhibition of macrosialin expression by C/EBPalpha-ER, indicating that JunB is not the only target relevant to inhibition of monopoiesis by C/EBPalpha. ..
- Kaeferstein A, Krug U, Tiesmeier J, Aivado M, Faulhaber M, Stadler M, et al. The emergence of a C/EBPalpha mutation in the clonal evolution of MDS towards secondary AML. Leukemia. 2003;17:343-9 pubmed..The emergence of a bast clone carrying a C/EBPalpha mutation at relapse indicates that this mutation may confer a growth advantage in a myeloid cell with an established differentiation block. ..
- Heath V, Suh H, Holman M, Renn K, Gooya J, Parkin S, et al. C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo. Blood. 2004;104:1639-47 pubmed..These findings show that C/EBPalpha deficiency results in hyperproliferation of HPCs and a block in the ability of multipotential progenitors to differentiate into bipotential granulocyte/macrophage progenitors and their progeny. ..
- Shim M, Smart R. Lithium stabilizes the CCAAT/enhancer-binding protein alpha (C/EBPalpha) through a glycogen synthase kinase 3 (GSK3)-independent pathway involving direct inhibition of proteasomal activity. J Biol Chem. 2003;278:19674-81 pubmed..These results demonstrate C/EBPalpha is degraded via a ubiquitin-dependent proteasomal pathway, and LiCl stabilizes C/EBPalpha through a GSK3-independent pathway involving direct inhibition of proteasome activity. ..
- Keeshan K, Santilli G, Corradini F, Perrotti D, Calabretta B. Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation. Blood. 2003;102:1267-75 pubmed
- Valverde A, Arribas M, Mur C, Navarro P, Pons S, Cassard Doulcier A, et al. Insulin-induced up-regulated uncoupling protein-1 expression is mediated by insulin receptor substrate 1 through the phosphatidylinositol 3-kinase/Akt signaling pathway in fetal brown adipocytes. J Biol Chem. 2003;278:10221-31 pubmed..These data provide strong evidence for an essential role of IRS-1 through the PI 3-kinase/Akt signaling pathway inducing UCP-1 gene expression by insulin. ..
- Snaddon J, Smith M, Neat M, Cambal Parrales M, Dixon McIver A, Arch R, et al. Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Genes Chromosomes Cancer. 2003;37:72-8 pubmed..In conclusion, mutation of CEBPA is a recurrent finding in AML and appears specific to the intermediate cytogenetic risk group patients. ..
- Wang Q, Cleaves R, Kummalue T, Nerlov C, Friedman A. Cell cycle inhibition mediated by the outer surface of the C/EBPalpha basic region is required but not sufficient for granulopoiesis. Oncogene. 2003;22:2548-57 pubmed..Inhibition of G1 progression using mimosine increased induction of late markers by G-CSF. Thus, both DNA binding and cell cycle arrest, mediated by opposite surfaces of the C/EBPalpha basic region, are required for granulopoiesis. ..
- Zheng R, Friedman A, Levis M, Li L, Weir E, Small D. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. Blood. 2004;103:1883-90 pubmed..Forced expression of C/EBPalpha was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBPalpha in this process. ..
- Muller C, Calkhoven C, Sha X, Leutz A. The CCAAT enhancer-binding protein alpha (C/EBPalpha) requires a SWI/SNF complex for proliferation arrest. J Biol Chem. 2004;279:7353-8 pubmed
- Ross S, Radomska H, Wu B, Zhang P, Winnay J, Bajnok L, et al. Phosphorylation of C/EBPalpha inhibits granulopoiesis. Mol Cell Biol. 2004;24:675-86 pubmed..Thus, myeloid development is partly regulated by an ERK1/2-mediated change in the conformation of C/EBPalpha that favors monocyte differentiation by blocking granulopoiesis. ..
- Cleaves R, Wang Q, Friedman A. C/EBPalphap30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding. Oncogene. 2004;23:716-25 pubmed..Variation in affinity for selected cis elements among isoforms may affect the biology of basic region-leucine zipper (bZIP) proteins. ..
- Wang G, Iakova P, Wilde M, Awad S, Timchenko N. Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity. Genes Dev. 2004;18:912-25 pubmed..These data provide a molecular basis for the development of liver tumors in which the activation of PI3K/Akt pathway neutralizes C/EBPalpha growth inhibitory activity. ..
- Nerlov C. C/EBPalpha mutations in acute myeloid leukaemias. Nat Rev Cancer. 2004;4:394-400 pubmed
- Schwieger M, Löhler J, Fischer M, Herwig U, Tenen D, Stocking C. A dominant-negative mutant of C/EBPalpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Blood. 2004;103:2744-52 pubmed
- Wiper Bergeron N, Wu D, Pope L, Schild Poulter C, Haché R. Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex. EMBO J. 2003;22:2135-45 pubmed..Recapitulation of the glucocorticoid effect by progestin treatment in the presence of the progesterone receptor ligand-binding domain suggests a conserved mechanism relevant to many aspects of steroid-mediated differentiation. ..