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FOXO transcription factors at the interface between longevity and tumor suppression
1Department of Genetics, Stanford University, CA 94305, USA.
Abstract:
A wide range of human diseases, including cancer, has a striking age-dependent onset. However, the molecular mechanisms that connect aging and cancer are just beginning to be unraveled. FOXO transcription factors are promising candidates to serve as molecular links between longevity and tumor suppression. These factors are major substrates of the protein kinase Akt. In the presence of insulin and growth factors, FOXO proteins are relocalized from the nucleus to the cytoplasm and degraded via the ubiquitin-proteasome pathway. In the absence of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest, stress resistance, or apoptosis. Stress stimuli also trigger the relocalization of FOXO factors into the nucleus, thus allowing an adaptive response to stress stimuli. Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity. Emerging evidence also suggests that FOXO factors play a tumor suppressor role in a variety of cancers. Thus, FOXO proteins translate environmental stimuli into changes in gene expression programs that may coordinate organismal longevity and tumor suppression.
Insights
FOXO transcription factors link aging and cancer by regulating genes involved in cell cycle arrest and apoptosis. Activating FOXO proteins promotes longevity and suppresses tumors, offering insights into age-related diseases.
Area of Science:
- Molecular Biology
- Genetics
- Aging Research
Background:
- Human diseases, including cancer, exhibit age-dependent onset.
- Molecular links between aging and cancer are under investigation.
- FOXO (Forkhead box O) transcription factors are implicated in longevity and tumor suppression.
Purpose of the Study:
- To explore the role of FOXO transcription factors as molecular links between aging and cancer.
- To understand how FOXO proteins integrate environmental signals to regulate gene expression.
- To investigate the connection between stress resistance, longevity, and tumor suppression mediated by FOXO factors.
Main Methods:
- Analysis of FOXO protein localization and degradation pathways.
- Investigating FOXO target gene regulation in response to growth factors and stress.
- Examining the impact of FOXO activation on lifespan in model organisms (worms and flies).
Main Results:
- FOXO proteins are regulated by the Akt kinase pathway, translocating to the nucleus in the absence of growth factors.
- Nuclear FOXO proteins upregulate genes promoting cell cycle arrest, stress resistance, and apoptosis.
- Activation of FOXO transcription factors in model organisms extends lifespan.
- Evidence suggests FOXO factors possess tumor suppressor functions in various cancers.
Conclusions:
- FOXO transcription factors act as crucial mediators between environmental stimuli and gene expression programs.
- These factors coordinate organismal longevity and tumor suppression, highlighting their significance in age-related diseases.
- FOXO proteins represent a key molecular link connecting the aging process with cancer development.
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