FOXOs and their roles in acute and chronic neurological disorders
Yasin Asadi1,2,3, Rozenn K Moundounga1,2,3, Anand Chakroborty1,2,3
1Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, United States.
Abstract:
The forkhead family of transcription factors of class O (FOXOs) consisting of four functionally related proteins, FOXO1, FOXO3, FOXO4, and FOXO6, are mammalian homologs of daf-16 in Caenorhabditis elegans and were previously identified as tumor suppressors, oxidative stress sensors, and cell survival modulators. Under normal physiological conditions, FOXO protein activities are negatively regulated by phosphorylation via the phosphoinositide 3-kinase (PI3K)-Akt pathway, a well-known cell survival pathway: Akt phosphorylates FOXOs to inactivate their transcriptional activity by relocalizing FOXOs from the nucleus to the cytoplasm for degradation. However, under oxidative stress or absent the cellular survival drive of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell growth arrest and cell death and altering mitochondrial homeostasis. FOXO gene expression is also regulated by other transcriptional factors such as p53 or autoregulation by their activities and end products. Here we summarize the structure, posttranslational modifications, and translocation of FOXOs linking to their transcriptional control of cellular functions, survival, and death, emphasizing their role in regulating the cellular response to some acute insults and chronic neurological disorders. This review will conclude with a brief section on potential therapeutic interventions that can be used to modulate FOXOs' activities when treating acute and chronic neurological disorders.
Insights
Forkhead box O (FOXO) proteins regulate cell survival and death. Their nuclear translocation under stress promotes cell death, offering therapeutic targets for neurological disorders.
Area of Science:
- Molecular Biology
- Cellular Biology
- Neuroscience
Background:
- Forkhead box O (FOXO) proteins are key regulators of cellular processes, including stress response, survival, and death.
- They are mammalian homologs of C. elegans DAF-16 and function as tumor suppressors and oxidative stress sensors.
- FOXO activity is tightly controlled by signaling pathways like PI3K-Akt, which regulates their localization and transcriptional function.
Purpose of the Study:
- To review the structure, modifications, and translocation of FOXO proteins.
- To elucidate the role of FOXOs in transcriptional control of cellular functions, survival, and death.
- To emphasize FOXOs' involvement in cellular responses to acute insults and chronic neurological disorders and discuss therapeutic interventions.
Main Methods:
- Literature review and synthesis of existing research on FOXO proteins.
- Analysis of FOXO structure, posttranslational modifications, and subcellular localization.
- Examination of FOXO-mediated gene regulation and cellular responses to stress and disease.
Main Results:
- FOXO proteins translocate to the nucleus under oxidative stress or absence of growth factors, activating genes that promote cell cycle arrest and apoptosis.
- FOXO activity is modulated by phosphorylation (e.g., via Akt) and other transcription factors (e.g., p53).
- FOXO dysregulation is implicated in acute insults and chronic neurological disorders, affecting mitochondrial homeostasis.
Conclusions:
- FOXO proteins play a critical role in cellular defense mechanisms and are implicated in neurological conditions.
- Modulating FOXO activity presents a potential therapeutic strategy for treating acute and chronic neurological disorders.
- Further research into FOXO regulation and function can lead to novel treatment approaches for neurological diseases.
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