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Mitogenic and oncogenic properties of the small G protein Rap1b
D L Altschuler1, F Ribeiro-Neto
1Department of Pharmacology, School of Medicine, University of Pittsburgh, PA 15261, USA. altschul@server.pharm.pitt.edu
Abstract:
It has been widely reported that the small GTP-binding protein Rap1 has an anti-Ras and anti-mitogenic activity. Thus, it is generally accepted that a normal physiological role of Rap1 proteins is to antagonize Ras mitogenic signals, presumably by forming nonproductive complexes with proteins that are typically effectors or modulators of Ras. Rap1 is activated by signals that raise intracellular levels of cAMP, a molecule that has long been known to exert both inhibitory and stimulatory effects on cell growth. We have now tested the intriguing hypothesis that Rap1 could have mitogenic effects in systems in which cAMP stimulates cell proliferation. The result of experiments addressing this possibility revealed that Rap1 has full oncogenic potential. Expression of Rap1 in these cells results in a decreased doubling time, an increased saturation density, and an unusual anchorage-dependent morphological transformation. Most significantly, however, Rap1-expressing cells formed tumors when injected into nude mice. Thus, we propose that the view that holds Rap1 as an antimitogenic protein should be restricted and conclude that Rap1 is a conditional oncoprotein.
Insights
The small GTP-binding protein Rap1, previously thought to inhibit cell growth, demonstrates full oncogenic potential. Rap1 acts as a conditional oncoprotein, promoting cell proliferation and tumor formation in specific contexts.
Area of Science:
- Cell Biology
- Molecular Oncology
- Signal Transduction
Background:
- The small GTP-binding protein Rap1 is widely recognized for its anti-Ras and anti-mitogenic activities.
- Its physiological role is presumed to involve antagonizing Ras-mediated mitogenic signals, potentially through forming nonproductive complexes.
- Rap1 activation is linked to increased intracellular cyclic adenosine monophosphate (cAMP) levels, which have complex effects on cell growth.
Purpose of the Study:
- To investigate the hypothesis that Rap1 may possess mitogenic effects in cellular systems where cAMP stimulates proliferation.
- To determine the oncogenic potential of Rap1 under conditions promoting cell proliferation.
Main Methods:
- Expression of Rap1 in cells where cAMP stimulates proliferation.
- Assessment of cellular proliferation parameters: doubling time and saturation density.
- Evaluation of morphological changes and anchorage dependence.
- Tumorigenicity assays in nude mice.
Main Results:
- Rap1 expression led to decreased doubling time and increased saturation density.
- Rap1-induced cells exhibited unusual anchorage-dependent morphological transformation.
- Significantly, Rap1-expressing cells formed tumors when injected into nude mice, indicating tumorigenic capacity.
Conclusions:
- The established view of Rap1 solely as an antimitogenic protein requires restriction.
- Rap1 exhibits full oncogenic potential and functions as a conditional oncoprotein in specific cellular contexts.
- These findings highlight the context-dependent role of Rap1 in cell growth regulation and cancer development.