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Transforming growth factor beta1 selectively regulates ferritin gene expression in malignant H-ras-transformed
1Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, ON, Canada.
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.
Insights
Transforming growth factor beta1 (TGF-beta1) alters ferritin gene expression in malignant cells. This study reveals TGF-beta1 post-transcriptionally stabilizes H-ferritin mRNA, suggesting a mechanism for growth factor-stimulated tumor growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor beta1 (TGF-beta1) typically inhibits cell growth but can stimulate proliferation in malignant cells.
- Malignant transformation often involves loss of TGF-beta1 growth inhibition and altered cellular responses.
- Ferritin plays roles in iron homeostasis and cell growth control, with its expression potentially linked to cancer progression.
Purpose of the Study:
- To investigate the relationship between TGF-beta1 regulation and ferritin gene expression during malignant transformation.
- To explore the mechanisms by which TGF-beta1 influences ferritin expression in H-ras-transformed cells.
Main Methods:
- Utilized a series of H-ras-transformed mouse 10 T 1/2 cell lines with varying malignant potential.
- Analyzed TGF-beta1-mediated changes in ferritin gene expression, focusing on H-ferritin.
- Investigated transcriptional and post-transcriptional regulatory mechanisms, including mRNA stability and protein synthesis inhibition.
Main Results:
- Malignant H-ras-transformed cells showed significant elevations in ferritin gene expression, particularly H-ferritin, upon TGF-beta1 treatment.
- TGF-beta1-induced H-ferritin gene expression occurred via post-transcriptional stabilization of H-ferritin mRNA, not transcriptional changes.
- Cycloheximide (protein synthesis inhibitor) increased H-ferritin mRNA levels and cooperated with TGF-beta1.
Conclusions:
- TGF-beta1 regulates ferritin gene expression in malignant H-ras transformed cells.
- The mechanism involves post-transcriptional stabilization of H-ferritin mRNA.
- Altered H-ferritin gene expression control may be a key factor in growth factor stimulation of malignant cells.