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Adenovirus E1A antagonizes both negative and positive growth signals elicited by transforming growth factor beta 1
R P de Groot1, O Kranenburg, L de Wit
1Laboratory for Molecular Carcinogenesis, Sylvius Laboratories, University of Leiden, The Netherlands.
Abstract:
Transforming growth factor beta 1 (TGF beta 1) is a cytokine capable of inhibiting or stimulating cell growth, depending on the nature of the target cell. Inhibition of cell growth by TGF beta 1 is thought to be mediated by TGF beta 1-induced changes in the expression and activity of cell cycle regulatory proteins like cyclin-dependent kinase (cdk) 2 and cdk4. Here we show that adenovirus E1A blocks growth inhibition by TGF beta 1. The activity of cdk2 was strongly inhibited by TGF beta 1 in control cells but not in E1A-expressing cells. Similarly, an early event in TGF beta 1 signaling, junB induction, was significantly reduced in E1A-expressing cells. E1A also interferes with growth stimulation of NRK cells by TGF beta 1, both in monolayer and in soft agar. In these cells, E1A also interferes with junB induction by TGF beta 1. Moreover, E1A abrogates TGF beta 1-induced production of an autocrine-acting platelet-derived growth factor-like activity. These results show that E1A can interfere with TGF beta 1-induced growth-inhibiting as well as growth-promoting signals.
Insights
Adenovirus E1A protein blocks transforming growth factor beta 1 (TGF-β1) signals. E1A interferes with both TGF-β1-induced cell growth inhibition and stimulation, impacting key cell cycle regulators.
Area of Science:
- Cell Biology
- Molecular Biology
- Virology
Background:
- Transforming growth factor beta 1 (TGF-β1) is a cytokine with dual roles in regulating cell growth, acting as either an inhibitor or stimulator.
- TGF-β1-mediated growth inhibition is linked to alterations in cell cycle regulatory proteins, including cyclin-dependent kinases (cdks).
Purpose of the Study:
- To investigate the effect of adenovirus E1A on TGF-β1 signaling pathways.
- To determine if E1A can modulate TGF-β1's dual functions in cell growth regulation.
Main Methods:
- Utilized adenovirus E1A-expressing cells and control cells for comparative analysis.
- Assessed the impact of TGF-β1 on cell cycle regulatory protein activity (cdk2).
- Monitored early signaling events like junB induction and autocrine growth factor production.
Main Results:
- Adenovirus E1A expression blocked TGF-β1-induced growth inhibition and cdk2 activity reduction.
- E1A significantly reduced TGF-β1-induced junB expression in both growth-inhibited and growth-stimulated cells.
- E1A interfered with TGF-β1-mediated growth stimulation in NRK cells and abrogated TGF-β1-induced production of platelet-derived growth factor-like activity.
Conclusions:
- Adenovirus E1A protein effectively interferes with both inhibitory and stimulatory signaling pathways induced by TGF-β1.
- E1A's interference impacts critical components of TGF-β1 signaling, including cell cycle regulation and autocrine growth factor production.