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Abstract:

The first and rate-controlling step of the haem biosynthetic pathway in mammals and fungi is catalysed by the mitochondrial-matrix enzyme 5-aminolaevulinate synthase (ALAS). The purpose of this work was to explore the molecular mechanisms involved in the cAMP regulation of rat housekeeping ALAS gene expression. Thus we have examined the ALAS promoter for putative transcription-factor-binding sites that may regulate transcription in a cAMP-dependent protein kinase (PKA)-induced context. Applying both transient transfection assays with a chloramphenicol acetyltransferase reporter gene driven by progressive ALAS promoter deletions in HepG2, and electrophoresis mobility-shift assays we have identified two putative cAMP-response elements (CREs) at positions - 38 and - 142. Functional analysis showed that both CRE-like sites were necessary for complete PKA induction, but only one for basal expression. Co-transfection with a CRE-binding protein (CREB) expression vector increased PKA-mediated induction of ALAS promoter transcriptional activity. However, in the absence of co-transfected PKA, CREB worked as a specific repressor for ALAS promoter activity. A CREB mutant deficient in a PKA phosphorylation site was unable to induce expression of the ALAS gene but could inhibit non-stimulated promoter activity. Furthermore, a DNA-binding mutant of CREB did not interfere with ALAS promoter basal activity. Site-directed-mutagenesis studies showed that only the nearest element to the transcription start site was able to inhibit the activity of the promoter. Therefore, we conclude that CREB, through its binding to CRE-like sites, mediates the effect of cAMP on ALAS gene expression. Moreover, we propose that CREB could also act as a repressor of ALAS transcription, but is able to reverse its role after PKA activation. Dephosphorylated CREB would interfere in a spatial-disposition-dependent manner with the transcriptional machinery driving inhibition of gene expression.

Registro:

Documento: Artículo
Título:5-aminolaevulinate synthase gene promoter contains two cAMP-response element (CRE)-like sites that confer positive and negative responsiveness to CRE-binding protein (CREB)
Autor:Giono, L.E.; Varone, C.L.; Cánepa, E.T.
Filiación:Laboratorio de Biologia Molec., Dipto. de Quimica Biologica, Universidad de Buenos Aires, Pabellón II Piso 4, 1428 Buenos Aires, Argentina
Palabras clave:Gene expression; Haem biosynthesis; Hepatic cell; Protein kinase A; Transcription factor; 5 aminolevulinate synthase; cyclic AMP; cyclic AMP dependent protein kinase; cyclic AMP responsive element binding protein; DNA; animal cell; article; cyclic AMP responsive element; enzyme activation; enzyme induction; enzyme phosphorylation; gene deletion; gene expression regulation; genetic transfection; heme synthesis; housekeeping gene; human; human cell; nonhuman; priority journal; promoter region; protein binding; protein DNA binding; rat; repressor gene; site directed mutagenesis; transcription regulation; 5-Aminolevulinate Synthetase; Animals; Binding Sites; CREB-Binding Protein; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Gene Expression; Humans; Mutation; Nuclear Proteins; Oligonucleotides, Antisense; Plasmids; Promoter Regions (Genetics); Rats; Signal Transduction; Trans-Activators; Transcription, Genetic; Tumor Cells, Cultured; Animalia; Fungi; Mammalia
Año:2001
Volumen:353
Número:2
Página de inicio:307
Página de fin:316
DOI: http://dx.doi.org/10.1042/0264-6021:3530307
Título revista:Biochemical Journal
Título revista abreviado:Biochem. J.
ISSN:02646021
CODEN:BIJOA
CAS:5-Aminolevulinate Synthetase, EC 2.3.1.37; CREB-Binding Protein, EC 2.3.1.48; CREBBP protein, human; Crebbp protein, rat; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases, EC 2.7.1.37; Nuclear Proteins; Oligonucleotides, Antisense; Trans-Activators
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02646021_v353_n2_p307_Giono

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Citas:

---------- APA ----------
Giono, L.E., Varone, C.L. & Cánepa, E.T. (2001) . 5-aminolaevulinate synthase gene promoter contains two cAMP-response element (CRE)-like sites that confer positive and negative responsiveness to CRE-binding protein (CREB). Biochemical Journal, 353(2), 307-316.
http://dx.doi.org/10.1042/0264-6021:3530307
---------- CHICAGO ----------
Giono, L.E., Varone, C.L., Cánepa, E.T. "5-aminolaevulinate synthase gene promoter contains two cAMP-response element (CRE)-like sites that confer positive and negative responsiveness to CRE-binding protein (CREB)" . Biochemical Journal 353, no. 2 (2001) : 307-316.
http://dx.doi.org/10.1042/0264-6021:3530307
---------- MLA ----------
Giono, L.E., Varone, C.L., Cánepa, E.T. "5-aminolaevulinate synthase gene promoter contains two cAMP-response element (CRE)-like sites that confer positive and negative responsiveness to CRE-binding protein (CREB)" . Biochemical Journal, vol. 353, no. 2, 2001, pp. 307-316.
http://dx.doi.org/10.1042/0264-6021:3530307
---------- VANCOUVER ----------
Giono, L.E., Varone, C.L., Cánepa, E.T. 5-aminolaevulinate synthase gene promoter contains two cAMP-response element (CRE)-like sites that confer positive and negative responsiveness to CRE-binding protein (CREB). Biochem. J. 2001;353(2):307-316.
http://dx.doi.org/10.1042/0264-6021:3530307