RESUMEN
Activity of FOXO (forkhead box O) transcription factors is inhibited by growth factor-PI3K (phosphoinositide 3-kinase)-PKB (protein kinase B)/Akt signalling to control a variety of cellular processes including cell cycle progression. Through comparative analysis of a number of microarray datasets we identified a set of genes commonly regulated by FOXO proteins and PI3K-PKB/Akt, which includes CTDSP2 (C-terminal domain small phosphatase 2). We validated CTDSP2 as a genuine FOXO target gene and show that ectopic CTDSP2 can induce cell cycle arrest. We analysed transcriptional regulation after CTDSP2 expression and identified extensive regulation of genes involved in cell cycle progression, which depends on the phosphatase activity of CTDSP2. The most notably regulated gene is the CDK (cyclin-dependent kinase) inhibitor p21(Cip1/Waf1) and in the present study we show that p21(Cip1/Waf1) is partially responsible for the cell cycle arrest through decreasing cyclin-CDK activity. Our data suggest that CTDSP2 induces p21(Cip1/Waf1) through increasing the activity of Ras. As has been described previously, Ras induces p21(Cip1/Waf1) through p53-dependent and p53-independent pathways and indeed both p53 and MEK inhibition can mitigate the CTDSP2-induced p21(Cip1/Waf1) mRNA up-regulation. In support of Ras activation by CTDSP2, depletion of endogenous CTDSP2 results in reduced Ras activity and thus CTDSP2 seems to be part of a larger set of genes regulated by FOXO proteins, which increase growth factor signalling upon FOXO activation.
Asunto(s)
Puntos de Control del Ciclo Celular/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Proteínas ras/metabolismo , Animales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/fisiología , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Células 3T3 NIH , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas Fosfatasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transcripción Genética/fisiología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas ras/genéticaRESUMEN
Aging is characterized by the general decline in tissue and body function and the increased susceptibility to age-related pathologies, such as cancer. To maintain optimal tissue and body function, organisms have developed complex mechanisms for tissue homeostasis. Importantly, it is becoming apparent that these same mechanisms when deregulated also result in the development of age-related disease. The build in fail safe mechanisms of homeostasis, which prevent skewing toward disease, themselves contribute to aspects of aging. Thus, longevity is limited by an intrinsic trade-off between optimal tissue function and disease. Consequently, aging and age-related diseases, such as cancer and diabetes are driven by the same genetic determinants. Illustrative in this respect is the insulin/IGF-1 signaling pathway acting through PI3K/PKB and FOXO. Loss of PKB signaling contributes to diabetes, whereas gain of function of PKB drives cancer. Enhanced FOXO activity, at least in model organism contributes to extended lifespan and acts as a tumor suppressive mechanism. Here, we focus on the linkage between PKB and FOXO as a central switch in contributing to tissue homeostasis and age-related diseases in particular cancer. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging.
Asunto(s)
Envejecimiento/metabolismo , Factores de Transcripción Forkhead/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Proteínas de Ciclo Celular/metabolismo , Proteína Forkhead Box O1 , Humanos , Modelos Biológicos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K signaling, all of which must be carefully balanced for tumor cells to thrive.Significance: FOXO proteins are not solely tumor suppressors, but also support tumor growth and metastasis by regulating a multitude of cellular processes essential for tumorigenesis. Cancer Res; 78(9); 2356-69. ©2018 AACR.