title: Transforming growth factor beta1 selectively regulates ferritin gene expression in malignant H-ras-transformed fibrosarcoma cell lines.
abstract: Transforming growth factor beta1 is an important growth regulator in many cell types, usually exerting a negative effect on cellular growth. Inhibition of DNA synthesis and cell proliferation is frequently lost during malignant transformation, and in some cases, tumor cell proliferation is actually stimulated by TGF-beta1. The present study demonstrates a novel link between alterations in TGF-beta1 regulation during malignant conversion, and the expression of ferritin, an important activity involved in a number of biological functions including iron homeostasis and cell-growth control. A series of H-ras-transformed mouse 10 T 1/2 cell lines, exhibiting increasing malignant potential, was investigated for possible TGF-beta1-mediated changes in ferritin gene expression. Selective induction of gene expression was observed, since only H-ras-transformed cells with malignant potential exhibited marked elevations in ferritin gene expression, in particular, alterations in H-ferritin gene expression. The regulation of H-ferritin gene expression in response to TGF-beta1 did not involve alterations in transcription, but occurred through mechanisms of post-transcriptional stabilization of the H-ferritin mRNA. Additionally, evidence was obtained for a cycloheximide-sensitive regulator of H-ferritin gene expression, since the presence of this protein synthesis inhibitor increased H-ferritin message levels, and in combination with TGF-beta1, cooperated in an additive manner to augment H-ferritin gene expression. These results show for the first time that TGF-beta1 can regulate ferritin gene expression in malignant H-ras transformed cells, and suggest a mechanism for growth factor stimulation of malignant cells, in which early alterations in the control of H-ferritin gene expression are important.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Lo
authors.forename: R A
authors.initials: RA
authors.lastname: Hurta
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D016895:Culture Media, Serum-Free; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005293:Ferritins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics*; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D016895:Culture Media, Serum-Free; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003609:Dactinomycin; D005293:Ferritins; D003513:Cycloheximide; D012264:Ribonucleotide Reductases