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Cell cycle and death control: long live Forkheads
Boudewijn M T Burgering1, Geert J P L Kops
1Dept Physiological Chemistry and Centre for Biomedical Genetics, University Medical Centre Utrecht, Stratenum, The Netherlands. b.m.t.burgering@med.uu.nl
Abstract:
The FOXO family of Forkhead transcription factors, FKHR (FOXO1), FKHR-L1 (FOXO3a) and AFX (FOXO4), are regulated by the phosphoinositide-3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) pathway. Direct phosphorylation by PKB results in cytoplasmic retention and inactivation, inhibiting the expression of FOXO-regulated genes, which control the cell cycle, cell death, cell metabolism and oxidative stress. This pathway appears to be well conserved throughout evolution. In the nematode Caenorhabditis elegans, it affects lifespan and controls dauer formation. Recent discoveries about FOXO regulation by PI3K-PKB signalling suggest that the PI3K-PKB-FOXO pathway might participate in similar processes in higher eukaryotes.
Insights
The phosphoinositide-3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) pathway regulates FOXO transcription factors, impacting cell functions. This conserved pathway influences lifespan and development in organisms like C. elegans and may affect similar processes in higher eukaryotes.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The FOXO family of transcription factors (FOXO1, FOXO3a, FOXO4) plays a crucial role in regulating cellular processes.
- These factors are key targets of the phosphoinositide-3-kinase-protein-kinase-B (PI3K-PKB/c-Akt) signaling pathway.
- PKB-mediated phosphorylation leads to FOXO inactivation and cytoplasmic localization, thereby controlling gene expression.
Purpose of the Study:
- To elucidate the regulatory mechanisms of the PI3K-PKB/c-Akt pathway on FOXO transcription factors.
- To explore the conserved functions of this pathway across different species.
- To investigate the potential role of the PI3K-PKB-FOXO pathway in higher eukaryotes.
Main Methods:
- Review of existing literature on FOXO transcription factors and PI3K-PKB/c-Akt signaling.
- Comparative analysis of pathway conservation in model organisms, including C. elegans.
- Exploration of FOXO-regulated gene functions in cell cycle, cell death, metabolism, and oxidative stress.
Main Results:
- The PI3K-PKB/c-Akt pathway directly phosphorylates and inactivates FOXO transcription factors.
- FOXO-regulated genes are critical for cell cycle control, apoptosis, metabolism, and oxidative stress response.
- The pathway's role in regulating lifespan and dauer formation in C. elegans highlights its evolutionary conservation.
Conclusions:
- The PI3K-PKB-FOXO signaling axis is a fundamental pathway conserved across evolution.
- Understanding this pathway provides insights into cellular regulation and potential therapeutic targets.
- Further research is warranted to fully understand the implications of this pathway in higher eukaryotes.