Retinol induces the ERK1/2-dependent phosphorylation of CREB through a pathway involving the generation of reactive oxygen species in cultured Sertoli cells.
The ability to regulate cell cycle progression and apoptosis through the activation of nuclear receptors and gene transcription has been generally accepted as a potential chemopreventive and therapeutic property of retinoids. However, recent studies suggest that retinol and related compounds can exert rapid and non-genomic effects, which may increase the production of reactive oxygen species (ROS) and lead to cell cycle disruption and malignant transformation. In this work, we report that, in Sertoli cells, retinol (7 microM) induces the Src-dependent activation of ERK1/2 MAPK and the ERK1/2-mediated phosphorylation of the transcription factor CREB. We found that these retinol-induced effects were completely blocked by the antioxidant Trolox 100 microM (a hydrophilic analogue of alpha-tocopherol), the hydroxyl radical scavenger mannitol (1 mM) and the addition of native superoxide dismutase (200 U/ml), and also that retinol increased the production of ROS and several other parameters indicative of oxidative stress during the same incubation periods in which ERK1/2 and CREB were phosphorylated. The activation of the ERK1/2-CREB pathway appears to be involved in the onset of some of the malignant effects caused by retinol in Sertoli cells since inhibition of ERK1/2 activation blocked the retinol-induced cell transformation and proliferation.
Gelain
Daniel P
DP
Centro de Estudos em Estresse Oxidativo, Brazil. dgelain@yahoo.com.br
Cammarota
Martín
M
Zanotto-Filho
Alfeu
A
de Oliveira
Ramatis B
RB
Dal-Pizzol
Felipe
F
Izquierdo
Iván
I
Bevilaqua
Lia R M
LR
Moreira
José C F
JC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012708:Sertoli Cells / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism*; D014801:Vitamin A / Q000494:pharmacology*
D000975:Antioxidants; D017362:Cyclic AMP Response Element-Binding Protein; D005419:Flavonoids; D013481:Superoxides; D014801:Vitamin A; D004247:DNA; D016392:Proto-Oncogene Proteins pp60(c-src); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one