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Multiple ras effector pathways contribute to G(1) cell cycle progression
1Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
The Journal of Biological Chemistry
|July 27, 1999
Summary
Ras signaling pathways are crucial for cell cycle progression. Multiple Ras effectors, including PI 3-kinase, Ral-GDS, and Raf, cooperate to regulate cyclin D1 expression and drive G1 phase advancement.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Ras proteins activate multiple signaling pathways controlling cell growth.
- The precise mechanisms by which Ras effectors regulate the G1 phase of the cell cycle remain incompletely understood.
- While extracellular-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) is linked to early cyclin D1 induction, its role during maximal cyclin D1 expression in late G1 is unclear.
Purpose of the Study:
- To investigate the roles of phosphatidylinositol 3-kinase (PI 3-kinase) and Ral-GDS effector pathways in G1 progression.
- To compare the contribution of PI 3-kinase and Ral-GDS pathways with the established Raf/MAPK pathway in regulating cell cycle progression.
- To elucidate the specific Ras effector pathways involved in cyclin D1 induction and G1 phase advancement.
Main Methods:
- Utilized NIH 3T3 fibroblasts stimulated with serum to study cell cycle progression.
- Assessed the requirement of PI 3-kinase activity for cyclin D1 expression and S phase entry.
- Investigated the role of Akt/PKB and Rac in mediating PI 3-kinase-induced cyclin D1 transcription and E2F activity.
- Examined the effects of activated Ral-GDS-like factor and Raf on cyclin D1 transcription and E2F activity, including their synergistic interactions with PI 3-kinase.
Main Results:
- PI 3-kinase activity is essential for endogenous cyclin D1 expression and subsequent S phase entry in serum-stimulated quiescent fibroblasts.
- Activated PI 3-kinase promotes cyclin D1 transcription and E2F activity, partly through the Akt/PKB kinase and to a lesser extent through the Rho GTPase Rac.
- Both activated Ral-GDS-like factor and Raf stimulate cyclin D1 transcription and E2F activity, working synergistically with PI 3-kinase.
Conclusions:
- Multiple Ras effector pathways, including PI 3-kinase, Ral-GDS, and Raf, cooperate to regulate cyclin D1 expression and promote G1 phase progression.
- PI 3-kinase, particularly via Akt/PKB, plays a significant role in mediating Ras-dependent cyclin D1 induction and cell cycle advancement.
- These findings highlight the complex interplay of Ras signaling networks in controlling cell cycle machinery.