Downregulation of C-Jun Expression by Transcription Factor C/EBPalpha is Critical for Granulocytic Lineage Commitment

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2002 Nov 26

PMID 12446786

Citations 18

Authors

Janki Rangatia

Rajani Kanth Vangala

Nicolai Treiber

Pu Zhang

Hanna Radomska

Daniel G Tenen

Wolfgang Hiddemann

Gerhard Behre

Affiliations

Soon will be listed here.

Abstract

The transcription factor C/EBPalpha is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and C/EBPalpha can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPalpha knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPalpha knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPalpha downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPalpha expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPalpha. C/EBPalpha and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPalpha-induced granulocytic differentiation. Thus, we propose a model in which C/EBPalpha needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.

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References

Clayton A, Rose S, Barratt M, Mahadevan L . Phosphoacetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon gene activation. EMBO J. 2000; 19(14):3714-26. PMC: 313972. DOI: 10.1093/emboj/19.14.3714. View

Wei P, Inamdar N, Vedeckis W . Transrepression of c-jun gene expression by the glucocorticoid receptor requires both AP-1 sites in the c-jun promoter. Mol Endocrinol. 1998; 12(9):1322-33. DOI: 10.1210/mend.12.9.0158. View

Pabst T, Mueller B, Zhang P, Radomska H, Narravula S, Schnittger S . Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001; 27(3):263-70. DOI: 10.1038/85820. View

Pabst T, Mueller B, Harakawa N, Schoch C, Haferlach T, Behre G . AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001; 7(4):444-51. DOI: 10.1038/86515. View

Burel S, Harakawa N, Zhou L, Pabst T, Tenen D, Zhang D . Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. Mol Cell Biol. 2001; 21(16):5577-90. PMC: 87279. DOI: 10.1128/MCB.21.16.5577-5590.2001. View

Gombart A, Hofmann W, Kawano S, Takeuchi S, Krug U, Kwok S . Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood. 2002; 99(4):1332-40. DOI: 10.1182/blood.v99.4.1332. View

Reddy V, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala R . Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood. 2002; 100(2):483-90. DOI: 10.1182/blood.v100.2.483. View

Behre G, Singh S, Liu H, Bortolin L, Christopeit M, Radomska H . Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248. J Biol Chem. 2002; 277(29):26293-9. DOI: 10.1074/jbc.M202301200. View

Vangala R, Heiss-Neumann M, Rangatia J, Singh S, Schoch C, Tenen D . The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2002; 101(1):270-7. DOI: 10.1182/blood-2002-04-1288. View

10.

Calabretta B . Dissociation of c-fos induction from macrophage differentiation in human myeloid leukemic cell lines. Mol Cell Biol. 1987; 7(2):769-74. PMC: 365133. DOI: 10.1128/mcb.7.2.769-774.1987. View

11.

Sariban E, Mitchell T, Rambaldi A, Kufe D . c-sis but not c-fos gene expression is lineage specific in human myeloid cells. Blood. 1988; 71(2):488-93. View

12.

Angel P, Allegretto E, Okino S, Hattori K, Boyle W, Hunter T . Oncogene jun encodes a sequence-specific trans-activator similar to AP-1. Nature. 1988; 332(6160):166-71. DOI: 10.1038/332166a0. View

13.

Landschulz W, Johnson P, McKnight S . The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988; 240(4860):1759-64. DOI: 10.1126/science.3289117. View

14.

Lamph W, Wamsley P, Sassone-Corsi P, Verma I . Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988; 334(6183):629-31. DOI: 10.1038/334629a0. View

15.

Angel P, Hattori K, Smeal T, Karin M . The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988; 55(5):875-85. DOI: 10.1016/0092-8674(88)90143-2. View

16.

Sassone-Corsi P, Ransone L, Lamph W, Verma I . Direct interaction between fos and jun nuclear oncoproteins: role of the 'leucine zipper' domain. Nature. 1988; 336(6200):692-5. DOI: 10.1038/336692a0. View

17.

Landschulz W, Johnson P, McKnight S . The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science. 1989; 243(4899):1681-8. DOI: 10.1126/science.2494700. View

18.

Bertani A, Polentarutti N, Sica A, Rambaldi A, Mantovani A, Colotta F . Expression of c-jun protooncogene in human myelomonocytic cells. Blood. 1989; 74(5):1811-6. View

19.

Gramigni C, Penco S, Bianchi-Scarra G, Ravazzolo R, Garre C . An upstream negative regulatory element in human granulocyte-macrophage colony-stimulating factor promoter is recognised by AP1 family members. FEBS Lett. 1998; 440(1-2):119-24. DOI: 10.1016/s0014-5793(98)01443-4. View

20.

Behre G, Smith L, Tenen D . Use of a promoterless Renilla luciferase vector as an internal control plasmid for transient co-transfection assays of Ras-mediated transcription activation. Biotechniques. 1999; 26(1):24-6, 28. DOI: 10.2144/99261bm03. View