Enhanced expression of procollagenase in ataxia-telangiectasia and xeroderma pigmentosum fibroblasts.
Ataxia-telangiectasia and xeroderma pigmentosum are human hereditary diseases in which patients are cancer prone and demonstrate increased sensitivity to DNA damage by ionizing and ultraviolet radiation, respectively. In culture, both ataxia-telangiectasia and xeroderma pigmentosum skin fibroblasts show increased synthesis and secretion of the extracellular matrix proteins fibronectin and collagen. To determine whether these differences in protein production result from fundamental abnormalities in regulation of genes associated with cellular interactions, we compared the effects of trifluoperazine and 12-O-tetradecanoylphorbol-13-acetate on expression of the extracellular matrix-degrading metalloproteinases, procollagenase and prostromelysin, by normal, ataxia-telangiectasia, and xeroderma pigmentosum fibroblasts. After trifluoperazine treatment the overall levels of these metalloproteinases were much greater in three ataxia-telangiectasia cell strains and in cells from xeroderma pigmentosum complementation groups A and D than in normal cells. In contrast, cells from xeroderma pigmentosum complementation group C produced only slightly more procollagenase than normal cells. 12-O-tetradecanoylphorbol-13-acetate also induced higher than normal levels of procollagenase in some ataxia-telangiectasia and xeroderma pigmentosum strains, but less than that induced by trifluoperazine. Because increased extracellular accumulation of matrix-degrading enzymes has long been implicated in metastatic progression, this altered expression of procollagenase and prostromelysin in ataxia-telangiectasia and xeroderma pigmentosum cells could play an important role in the pathogenesis of various tumors in individuals with these genetic diseases.
Aggeler
J
J
Laboratory of Radiobiology and Environmental Health, University of California, San Francisco 94143.
Murnane
J P
JP
D001260:Ataxia Telangiectasia / Q000201:enzymology* / Q000235:genetics; D017364:Collagenases; D004792:Enzyme Precursors / Q000096:biosynthesis* / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D003012:Microbial Collagenase / Q000096:biosynthesis* / Q000378:metabolism; D012867:Skin / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014983:Xeroderma Pigmentosum / Q000201:enzymology* / Q000235:genetics
D004792:Enzyme Precursors; D014268:Trifluoperazine; D017364:Collagenases; C022440:procollagenase; D003012:Microbial Collagenase; D013755:Tetradecanoylphorbol Acetate