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Interaction of nuclear proteins with an AP‐1/CRE‐like promoter sequence in the human TNF‐ α gene
Author(s) -
Newell Christine L.,
Deisseroth Albert B.,
LopezBerestein Gabriel
Publication year - 1994
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.56.1.27
Subject(s) - biology , transcription factor , microbiology and biotechnology , binding site , promoter , binding protein , response element , protein kinase a , tumor necrosis factor alpha , gene , transcription (linguistics) , nuclear protein , kinase , gene expression , biochemistry , immunology , linguistics , philosophy
Abstract The tumor necrosis factor α (TNF‐ α ) promoter contains an AP‐l/CRE‐like binding site, TGAGCTCA. AP‐1 elements generally transduce signals involving protein kinase C; the CRE site mediates a cAMP response, involving protein kinase A. Thus, this element has the potential to receive signals through divergent signaling pathways. Nuclear protein binding studies using extracts from THP‐1 monocytic cells treated with lipopolysaccharide (LPS), which stimulates, or dexamethasone (Dex) or pentoxifylline (PTX), which inhibit TNF production, respectively, suggest that two lowmobility complexes could be involved in regulation through this promoter region. PTX and Dex increase binding of both these complexes compared with untreated cells; approximately 2 hours after LPS induction, the upper complex becomes undetectable. This upper complex is composed of ATF2 (activating transcription factor 2, a cyclic AMP responsive element binding protein) homodimers; the lower is a heterodimer of jun/ATF2. LPS induces c‐ jun and thus may enhance formation of jun/ATF2 complexes, which could be activating complexes. In this case, the simultaneous presence of both complexes, which would occur in the presence of Dex or PTX, could reduce the amount of TNF transcription through competitive binding. Through in vitro competitive binding studies comparing the binding affinities of the TNF promoter sequence and a consensus CRE, we further suggest how variation of endogenous binding sequences from consensus may be an important property for regulatory control of particular genes J. Leukoc. Biol. 56: 27–35; 1994.