Induction of metallothionein and other mRNA species by carcinogens and tumor promoters in primary human skin fibroblasts.

Abstract

We used nucleic acid hybridization and cDNA cloning techniques to isolate human sequences that respond to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). These clones were used as probes to examine changes of gene expression that occurred after the proliferation of exponentially growing primary human fibroblasts was arrested. Transcript levels detected by these probes were increased coordinately by treatment of the cells with UV light, mitomycin C, TPA, or the UV light-induced extracellular protein synthesis-inducing factor EPIF (M. Schorpp, U. Mallick, H. J. Rahmsdorf, and P. Herrlich, Cell 37: [861][862][863][864][865][866][867][868] 1984). Proteins coded for by these transcripts were characterized by hybrid-promoted translation and by cDNA sequencing. One of the cDNA clones was homologous to the metallothionein Ila gene, and one set of related clones selected RNA for the secreted TPA-inducible protein XHF1

Metallothionein expression in human breast cancer

“…This study confirms metallothionein overexpression in invasive breast carcinoma and further, our finding of no significant association between metallothionein and tumour size suggests that where overexpression does occur it does so early in the lifetime of the tumour, possibly during carcinogenesis. This would be consistent with previous reports of metallothionein induction occuring during carcinogenesis (Angel et al, 1986) and ultraviolet irradiation and a recent observation of increased metallothionein expression in breast epithelial hyperplasias and ductal carcinoma in situ (Bier et al, 1994), but does not necessarily imply a causative role. With their affinity to bind potentially carcinogenic metals (e.g.…”

Downregulation of metallothionein-IIA expression occurs at immortalization

“…One possibility is that MT-IIA could be involved in maintaining the limited lifespan phenotype, for example, by decreasing the activity of proteins required for DNA replication, telomere maintenance, and cell division. Since MTs may provide protection against DNA damage (Angel et al, 1986;Goncharova and Rossman, 1994), another possibility is that MT-IIA downregulation could facilitate the occurrence of a mutation required for immortalization.…”

The Activation of the Rat Copper/Zinc Superoxide Dismutase Gene by Hydrogen Peroxide through the Hydrogen Peroxide-responsive Element and by Paraquat and Heat Shock through the Same Heat Shock Element

“…Active oxygens are suggested to be involved in inflammatory responses; the activations by H 2 O 2 of c-fos, c-jun, and egr-1, which activate the expression of cellular genes, are probably essential for these responses. DNA damaging agents have been reported to activate c-fos and AP1-inducible genes such as those for collagenase and metallothionein (31). Active oxygens such as O 2 .…”