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The potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) induces activator protein-1 (AP-1) transcription factors, early response genes involved in a diverse set of transcriptional regulatory processes, and protein kinase C (PKC) activity. This work was designed to explore the signal transduction pathways involved in TPA regulation of 5-aminolevulinate synthase (ALAS) gene expression, the mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. We have previously reported that TPA causes repression of ALAS gene, but the signaling pathways mediating this effect remain elusive. The present study investigates the role of different cascades often implicated in the propagation of phorbol ester signaling. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in human hepatoma HepG2 cells. In these experimental conditions, we analyzed TPA action upon endogenous ALAS mRNA levels, as well as the promoter activity of a fusion reporter construct, harboring the TPA-responsive region of ALAS gene driving chloramphenicol acetyl transferase gene expression. We demonstrated that the participation of α isoform of PKC, phosphatidylinositol 3-kinase (PI3K), extracellular-signal regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) is crucial for the end point response. Remarkably, in this case, ERK activation is achieved in a Ras/Raf/MEK-independent manner. We also propose that p90RSK would be a convergent point between PI3K and ERK pathways. Furthermore, we elucidated the crosstalk among the components of the cascades taking part in TPA-mediated ALAS repression. Finally, by overexpression of a constitutively active p90RSK and the coactivator, cAMP-response element protein (CREB)-binding protein (CBP), we reinforced our previous model, that implies competition between AP-1 and CREB for CBP. © 2005 Elsevier Inc. All rights reserved.


Documento: Artículo
Título:Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways
Autor:Guberman, A.S.; Scassa, M.E.; Cánepa, E.T.
Filiación:Lab. de Biología Molecular, Depto. de Quím. Biol., Ciudad Universitaria, 1428 Buenos Aires, Argentina
Palabras clave:12-O-Tetradecanoylphorbol-13-acetate; 5-Aminolevulinate synthase; c-Jun N-terminal kinase; Extracellular-signal regulated kinase; Phosphatidyl inositol 3-kinase; Protein phosphorylation; Regulation of gene expression; Signal transduction; Tumor promoter; 2 (2 amino 3 methoxyphenyl)chromone; 5 aminolevulinate synthase; anthra[1,9 cd]pyrazol 6(2h) one; chloramphenicol acetyltransferase; cyclic AMP responsive element binding protein binding protein; heme; mevinolin; mitochondrial enzyme; mitogen activated protein kinase 1; pd 152440; phorbol 13 acetate 12 myristate; phorbol ester; phosphatidylinositol 3 kinase; protein farnesyltransferase inhibitor; protein kinase C alpha; Raf protein; Ras protein; regulator protein; stress activated protein kinase; tumor promoter; wortmannin; article; catalysis; cell membrane permeability; controlled study; enzyme activation; enzyme regulation; gene activity; gene expression; gene repression; hepatoma cell; human; human cell; priority journal; reporter gene; signal transduction
Página de inicio:285
Página de fin:296
Título revista:Archives of Biochemistry and Biophysics
Título revista abreviado:Arch. Biochem. Biophys.
CAS:2 (2 amino 3 methoxyphenyl)chromone, 167869-21-8; 5 aminolevulinate synthase, 9037-14-3; anthra[1,9 cd]pyrazol 6(2h) one, 129-56-6; chloramphenicol acetyltransferase, 9040-07-7; cyclic AMP responsive element binding protein binding protein, 190209-80-4; heme, 14875-96-8; mevinolin, 75330-75-5; mitogen activated protein kinase 1, 137632-08-7; phorbol 13 acetate 12 myristate, 16561-29-8; phosphatidylinositol 3 kinase, 115926-52-8; stress activated protein kinase, 155215-87-5; wortmannin, 19545-26-7


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---------- APA ----------
Guberman, A.S., Scassa, M.E. & Cánepa, E.T. (2005) . Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways. Archives of Biochemistry and Biophysics, 436(2), 285-296.
---------- CHICAGO ----------
Guberman, A.S., Scassa, M.E., Cánepa, E.T. "Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways" . Archives of Biochemistry and Biophysics 436, no. 2 (2005) : 285-296.
---------- MLA ----------
Guberman, A.S., Scassa, M.E., Cánepa, E.T. "Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways" . Archives of Biochemistry and Biophysics, vol. 436, no. 2, 2005, pp. 285-296.
---------- VANCOUVER ----------
Guberman, A.S., Scassa, M.E., Cánepa, E.T. Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways. Arch. Biochem. Biophys. 2005;436(2):285-296.