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Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1
M F Olson1, H F Paterson, C J Marshall
1CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
Abstract:
Small GTPases act as molecular switches in intracellular signal-transduction pathways. In the case of the Ras family of GTPases, one of their most important roles is as regulators of cell proliferation, and the mitogenic response to a variety of growth factors and oncogenes can be blocked by inhibiting Ras function. But in certain situations, activation of Ras signalling pathways arrests the cell cycle rather than causing cell proliferation. Extracellular signals may trigger different cellular responses by activating Ras-dependent signalling pathways to varying degrees. Other signalling pathways could also influence the consequences of Ras signalling. Here we show that when signalling through the Ras-related GTPase Rho is inhibited, constitutively active Ras induces the cyclin-dependent-kinase inhibitor p21Waf1/Cip1 and entry into the DNA-synthesis phase of the cell cycle is blocked. When Rho is active, induction of p21Waf1/Cip1 by Ras is suppressed and Ras induces DNA synthesis. Cells that lack p21Waf1/Cip1 do not require Rho signalling for the induction of DNA synthesis by activated Ras, indicating that, once Ras has become activated, the primary requirement for Rho signalling is the suppression of p21Waf1/Cip1 induction.
Insights
Small GTPases like Ras regulate cell proliferation. This study reveals that Rho GTPase signaling is crucial for Ras to promote DNA synthesis by suppressing the cell cycle inhibitor p21Waf1/Cip1.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Small GTPases, including Ras, function as molecular switches in intracellular signaling pathways.
- Ras GTPases are key regulators of cell proliferation, mediating responses to growth factors and oncogenes.
- Ras signaling can paradoxically lead to cell cycle arrest instead of proliferation under certain conditions.
Purpose of the Study:
- To investigate the role of Rho GTPase signaling in mediating Ras-induced cell cycle progression.
- To elucidate the mechanism by which Ras signaling influences cell cycle entry, specifically DNA synthesis.
- To determine the interplay between Ras, Rho, and the cyclin-dependent kinase inhibitor p21Waf1/Cip1 in cell cycle regulation.
Main Methods:
- Utilized constitutively active Ras and inhibited Rho signaling in cellular models.
- Assessed the induction of p21Waf1/Cip1 (a cyclin-dependent kinase inhibitor) in response to Ras activation.
- Examined the requirement for Rho signaling in Ras-induced DNA synthesis, including in cells lacking p21Waf1/Cip1.
Main Results:
- Inhibition of Rho signaling led to Ras-induced p21Waf1/Cip1 and blocked DNA synthesis.
- Active Rho signaling suppressed Ras-induced p21Waf1/Cip1, thereby promoting Ras-induced DNA synthesis.
- Cells deficient in p21Waf1/Cip1 did not require Rho signaling for Ras-induced DNA synthesis.
Conclusions:
- Rho GTPase signaling is essential for Ras to promote DNA synthesis.
- The primary role of Rho signaling in activated Ras pathways is to suppress the induction of p21Waf1/Cip1.
- This finding clarifies a critical mechanism by which extracellular signals, via Ras and Rho, differentially regulate cell cycle progression.