Efects of growth hormone and cadmium on the transcription regulation of two metallothionein isoforms.
The effect of growth hormone (GH) and cadmium (Cd) on metallothionein (MT) expression was investigated in hepatoma cells. In fish the constitutive isoform MT-B and the metal-responsive MT-A are expressed. Real-time RT-PCR revealed that: Cd up-regulates mostly MT-A, GH slightly induces MT-B and the GH/Cd combination induces synergistically both MTs. Perturbations in Ca2+ levels suppressed or reduced the Cd-induction of MTs and abolished the GH/Cd synergy. Similar results were obtained by inhibition of tyrosine kinases. Also the signaling molecules recruited by the GH receptor responded differently to GH and Cd, with ERKs showing a synergistic activation upon GH/Cd. The following conclusions can be drawn: (1) cytosolic Ca2+ is mainly involved in MT-A regulation; (2) both Ca2+ and tyrosine phosphorylation are essential for Cd-induction and GH/Cd synergy on MTs. The synergy could depend on interactions in different signaling pathways, leading to a differential recruitment of MTF-1 and AP-1 transcription factors.
Vergani
Laura
L
Department of Biophysical Sciences and Technologies M. & O (DISTBIMO), University of Genoa, Largo Rosanna Benzi 10, 16132 Genova, Italy. Laura.Vergani@unige.it
Lanza
Cristina
C
Borghi
Cristina
C
Scarabelli
Linda
L
Panfoli
Isabella
I
Burlando
Bruno
B
Dondero
Francesco
F
Viarengo
Aldo
A
Gallo
Gabriella
G
D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017686:Oncorhynchus mykiss / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D000097809:Transcription Factor MTF-1
D002104:Cadmium; D002118:Calcium; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D008668:Metallothionein; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014443:Tyrosine; D000097809:Transcription Factor MTF-1