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The antiproliferative effect of type beta transforming growth factor occurs at a level distal from receptors for
Abstract:
Transforming growth factor-beta (TGF beta) from human platelets blocks the ability of Mv1Lu mink lung epithelial cells to grow in response to serum mitogens, epidermal growth factor (EGF), or insulin. The phenotypic response of Mv1Lu cells to TGF beta is characterized by a flat, very enlarged cell morphology and a markedly increased production and accumulation of extracellular matrix fibronectin. The ability of TGF beta to alter the ligand binding or signal transducing activity of mitogen receptors in Mv1Lu cells has been examined. In contrast to NRK-49F rat fibroblasts, Mv1Lu cells do not respond to TGF beta with a decrease in the affinity or a change in the number of cell surface receptors for EGF. Soluble extracts from Mv1Lu cells contain a protein kinase activity which selectively phosphorylates ribosomal protein S6; this S6 kinase activity is elevated severalfold minutes after exposure of cells to mitogens. This kinase activity has been used as the parameter to measure the signaling ability of EGF receptors and insulin receptors in cells treated with TGF beta. We find that TGF beta does not alter the basal level of S6 kinase activity or its elevation by EGF or insulin. In TGF beta-treated cells rendered insensitive to the growth-promoting action of EGF, the parameters of elevation of S6 kinase activity by EGF are similar to those of control, growth-competent cells. The results suggest that TGF beta inhibits cell proliferation by acting at a level distal from the receptors for growth-activating factors.
Insights
Transforming growth factor-beta (TGF-β) inhibits mink lung epithelial cell proliferation by affecting downstream signaling pathways, not by altering growth factor receptor activity. This suggests TGF-β acts distally to mitogen receptors.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Transforming growth factor-beta (TGF-β) is a potent regulator of cell growth and differentiation.
- Mv1Lu mink lung epithelial cells are sensitive to TGF-β, exhibiting altered morphology and extracellular matrix production.
- Understanding the precise mechanism of TGF-β's inhibitory action is crucial for cell growth regulation research.
Purpose of the Study:
- To investigate the mechanism by which TGF-β inhibits Mv1Lu cell proliferation.
- To determine if TGF-β affects the activity or signaling of epidermal growth factor (EGF) and insulin receptors.
- To elucidate the specific level at which TGF-β exerts its anti-proliferative effects.
Main Methods:
- Mv1Lu cells were treated with TGF-β and mitogens (EGF, insulin).
- Cell surface EGF receptor binding and affinity were assessed.
- Ribosomal protein S6 kinase activity was measured as an indicator of mitogen signaling.
Main Results:
- TGF-β treatment did not alter EGF receptor affinity or number in Mv1Lu cells.
- TGF-β did not affect basal or mitogen-induced S6 kinase activity.
- EGF-induced S6 kinase activation remained normal in TGF-β-treated cells resistant to EGF's growth-promoting effects.
Conclusions:
- TGF-β inhibits Mv1Lu cell proliferation through a mechanism distal to growth factor receptors.
- TGF-β does not interfere with the ligand binding or signal transduction of EGF and insulin receptors.
- The anti-proliferative effects of TGF-β are mediated by intracellular pathways downstream of receptor activation.