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CAMP/phorbol ester response element is involved in transcriptional regulation of the human replacement histone gene H3.3B.

ABSTRACT: The human histone H3.3B gene belongs to the group of replacement histone genes, which are up-regulated during differentiation of cells. Here we provide evidence that a cAMP response element/PMA response element (CRE/TRE) located in the proximal promoter contributes to the expression of the H3.3B gene. (1) Band shift and supershift analysis demonstrated the binding of AP-1 and transcription factors of the CRE-binding protein/activating-transcription-factor family to the H3.3B CRE/TRE. (2) Treatment of HeLa cells with PMA led to a 4-fold increase in H3. 3B mRNA levels within 2 h, whereas transcription of the cell cycle-dependent H3 histone genes remained constant. In contrast with PMA, cAMP did not affect H3.3B transcription. (3) PMA treatment of cells transiently transfected with H3.3B promoter constructs linked to a luciferase gene caused a 4-5-fold increase in reporter gene activity, whereas mutation of the CRE/TRE element abolished the PMA response. These results demonstrate that activation of the protein kinase C pathway by PMA results in an early up-regulation of H3.3B gene expression via the CRE/TRE element. Furthermore treatment with PMA apparently leads to differential induction of H3 histone subtype genes and this in turn can result in a remodelling of chromatin structure of cells before or during differentiation processes.

SUBMITTER: Witt O

PROVIDER: S-EPMC1219083 | biostudies-other | 1998 Feb

REPOSITORIES: biostudies-other

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Project description:Phorbol ester-mediated differentiation of THP-1 cells (a human monocytic cell line) into mature macrophages is associated with a transcriptional induction of apolipoprotein E (apoE) expression [Auwerx, Deeb, Brunzell, Peng and Chait (1988) Biochemistry 27, 2651-2655]. Endotoxin, on the other hand, which may also act through activation of protein kinase C, is a potent inhibitor of apoE expression in mouse macrophages [Werb and Chin (1983) J. Biol. Chem. 258, 10642-10648]. The present experiments examine the effect of phorbol ester, an activator of protein kinase C, on the apoE expression in mouse thioglycollate-elicited peritoneal macrophages. Phorbol ester inhibits apoE expression in a specific, time- and dose-dependent manner. A 75% inhibition in the rate of apoE secretion, but not that of total protein, was observed following a 4.5 h incubation with 160 nM phorbol ester, although nearly full inhibition was obtained with 40 nM. The changes in apoE secretion were paralleled by similar changes in apoE synthesis, indicating synthesis as the primary site of action. The decreased rates of apoE synthesis are shown not to be due to increased apoE degradation. The profound inhibition of apoE synthesis was not accompanied by significant changes in apoE mRNA levels at any concentration of phorbol ester (up to 16 microM), or length of treatment (up to 24 h), suggesting a post-transcriptional locus of regulation of apoE expression. Although the early changes in apoE synthesis correlate with increased microsomal protein kinase C activity, the suppression of apoE expression persists even during conditions of nearly complete (> 95%) loss of protein kinase C activity, suggesting that the direct or indirect effect of protein kinase C on apoE expression is mediated by a stable phosphorylated protein, or that the observed effects are mediated through a protein kinase C species that is not readily downregulated by phorbol esters. The presented studies clearly demonstrate the potential importance of the translational regulation of apoE expression through the protein kinase C signal transduction pathway.

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CAMP/phorbol ester response element is involved in transcriptional regulation of the human replacement histone gene H3.3B.

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