Nickel(II) induces alterations in EGF- and TGF-beta 1-mediated growth control during malignant transformation of human kidney epithelial cells.
We have previously described immortalization of normal human kidney epithelial cells by nickel(II) and the subsequent tumorigenic conversion by v-Ha-ras transfection. We report here that nickel(II) induces alterations in growth regulatory control. Normal human kidney epithelial cells (NHKE) were growth inhibited by transforming growth factor beta 1 (TGF-beta 1). This effect was abrogated in both the immortalized (IHKE) and transformed (THKE) cells. NHKE expressed approximately 4700 high-affinity binding sites/cell for TGF-beta 1. IHKE and THKE showed reduced binding of 47% and 44% relative to NHKE respectively. On the other hand, expression of epidermal growth factor (EGF) receptors was elevated in IHKE (260%) and THKE (236%) relative to NHKE, which expressed 1.5 x 10(5) receptors/cell. Preincubation of IHKE and THKE with TGF-beta 1 resulted in reduced EGF binding, whereas this binding was unaltered in NHKE. Exposure of human kidney epithelial cells to EGF led to tyrosine phosphorylation of the EGF receptor and other cellular proteins in the mol. wt range from 42 to > 300 kDa. The level of receptor phosphorylation induced by EGF reflected receptor expression. Tyrosine phosphorylated proteins appear to be identical in all three cell lines, and reach phosphorylation maxima independently of EGF receptor expression. These studies indicate that nickel carcinogenesis may involve changes in sets of genes important in normal growth regulation.
Mollerup
S
S
Department of Toxicology, National Institute of Occupational Health, Norway.
Rivedal
E
E
Mæhle
L
L
Haugen
A
A
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D009532:Nickel; D004247:DNA; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases