Study summary · research use only
Dynamic FoxO transcription factors
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This review describes the mammalian Forkhead box O (FoxO) transcription factors FoxO1, FoxO3a, FoxO4, and FoxO6, orthologs of Caenorhabditis elegans DAF-16. The authors state these proteins modulate expression of genes involved in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, and glucose metabolism. They describe multiple regulatory mechanisms: inhibitory phosphorylation by kinases such as Akt, SGK, IKK, and CDK2; activation by upstream regulators JNK and MST1 under stress; and counterbalancing by acetylases CBP and p300 and the deacetylase SIRT1. The review notes that polyubiquitylation of FoxO1 and FoxO3a leads to proteasomal degradation, whereas monoubiquitylation of FoxO4 facilitates nuclear localization and augments transcriptional activity. The authors state that dysregulation of these proteins may lead to disease such as cancer.
Abstract
Forkhead box O (FoxO) transcription factors FoxO1, FoxO3a, FoxO4 and FoxO6, the mammalian orthologs of Caenorhabditis elegans DAF-16, are emerging as an important family of proteins that modulate the expression of genes involved in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism and other cellular functions. FoxO proteins are regulated by multiple mechanisms. They undergo inhibitory phosphorylation by protein kinases such as Akt, SGK, IKK and CDK2 in response to external and internal stimuli. By contrast, they are activated by upstream regulators such as JNK and MST1 under stress conditions. Their activities are counterbalanced by the acetylases CBP and p300 and the deacetylase SIRT1. Also, whereas polyubiquitylation of FoxO1 and FoxO3a leads to their degradation by the proteasome, monoubiquitylation of FoxO4 facilitates its nuclear localization and augments its transcriptional activity. Thus, the potent functions of FoxO proteins are tightly controlled by complex signaling pathways under physiological conditions; dysregulation of these proteins may ultimately lead to disease such as cancer.
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