Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways

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 tr...

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Autores principales:	Guberman, A.S., Scassa, M.E., Cánepa, E.T.
Formato:	JOUR
Materias:	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
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00039861_v436_n2_p285_Guberman
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_00039861_v436_n2_p285_Guberman2023-10-03T13:57:02Z Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways Guberman, A.S. Scassa, M.E. Cánepa, E.T. 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 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00039861_v436_n2_p285_Guberman
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 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
topic_facet	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
description	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.
format	JOUR
author	Guberman, A.S. Scassa, M.E. Cánepa, E.T.
author_facet	Guberman, A.S. Scassa, M.E. Cánepa, E.T.
author_sort	Guberman, A.S.
title	Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways
title_short	Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways
title_full	Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways
title_fullStr	Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways
title_full_unstemmed	Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways
title_sort	repression of 5-aminolevulinate synthase gene by the potent tumor promoter, tpa, involves multiple signal transduction pathways
url	http://hdl.handle.net/20.500.12110/paper_00039861_v436_n2_p285_Guberman
work_keys_str_mv	AT gubermanas repressionof5aminolevulinatesynthasegenebythepotenttumorpromotertpainvolvesmultiplesignaltransductionpathways AT scassame repressionof5aminolevulinatesynthasegenebythepotenttumorpromotertpainvolvesmultiplesignaltransductionpathways AT canepaet repressionof5aminolevulinatesynthasegenebythepotenttumorpromotertpainvolvesmultiplesignaltransductionpathways
_version_	1782029213704912896

Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways

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