CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor

Liu, P; Kao, Timothy P.; Huang, Haojie

doi:10.1038/onc.2008.104

Cited by 142 publications

(108 citation statements)

References 56 publications

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“…CDK2 (47) and, more recently, CDK1 (48,49) were reported to regulate FOXO1 by phosphorylation on S249, which is unaltered in our phosphosite mutant. CDK2 phosphorylation on S249 leads to cytoplasmic localization and decreased activity in both wild-type and FOXO1;AAA in a p53-independent fashion as measured by target gene expression (47).…”

Section: Discussionmentioning

confidence: 95%

Differential Response of Glioma Cells to FOXO1-Directed Therapy

2009

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Gliomas are the most common adult primary brain tumors, and the most malignant form, glioblastoma multiforme, is invariably fatal. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is altered in most glioblastoma multiforme. PTEN, an important negative regulator of the PI3K-Akt pathway, is also commonly mutated in glioma, leading to constitutive activation of Akt. One ultimate consequence is phosphorylation and inactivation of FOXO forkhead transcription factors that regulate genes involved in apoptosis, cell cycle arrest, nutrient availability, DNA repair, stress, and angiogenesis. We tested the ability of a mutant FOXO1 factor that is not subject to Akt phosphorylation to overcome dysregulated PI3K-Akt signaling in two PTEN-null glioma cell lines, U87 and U251. Adenovirus-mediated gene transfer of the mutant FOXO1 successfully restored cell cycle arrest and induced cell death in vitro and prolonged survival in vivo in xenograft models of human glioma (33% survival at 1 year of animals bearing U251 tumors). However, U87 were much more resistant than U251 to mutant FOXO1-induced death, showing evidence of increased nuclear export and Aktindependent phosphorylation of FOXO1 at S249. A cyclindependent kinase 2 inhibitor decreased phosphorylation of S249 and rendered U87 cells significantly more susceptible to mutant FOXO1-induced death. Our results indicate that targeting FOXO1, which is at the convergence point of several growth factor receptor tyrosine kinase pathways, can effectively induce glioma cell death and inhibit tumor growth. They also highlight the importance of Akt-independent phosphorylation events in the nuclear export of FOXO1. [Cancer Res 2009;69(13):5433-40]

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Section: Discussionmentioning

confidence: 95%

Differential Response of Glioma Cells to FOXO1-Directed Therapy

2009

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“…Previous studies found that FOXO1 function was closely related with its phosphorylation and acetylation modification which determined its transcriptional activity (40)(41)(42)(43)(44). Recent studies found that microRNAs, such as miR-96 and miR-370, downregulated FOXO1 expression (28,29).…”

Section: Discussionmentioning

confidence: 97%

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Jin

Yang

et al. 2013

Oncology Reports

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The RNA-binding protein Quaking (QKI) is known to be essential for embryonic development and postnatal myelination. Forkhead box O1 (FOXO1) is a critical tumor suppressor for cell proliferation control. Dysregulation of FOXO1 expression has been observed in a variety of cancers. In the present study, we demonstrated that QKI decreased FOXO1 mRNA expression at the post-transcriptional level. QKI was able to bind the 3'UTR of FOXO1 mRNA directly and decreased its mRNA stability. To determine whether QKI-mediated post-transcriptional repression of FOXO1 indeed plays a role in cancer cells, we first detected both QKI and FOXO1 expression in four breast cancer cell lines. FOXO1 expression was extremely low in these cell lines, whereas QKI expression was relative high. Knockdown of QKI significantly restored FOXO1 expression. ATRA, an inducer of apoptosis or differentiation, dramatically enhanced FOXO1 expression while it repressed QKI expression. Importantly, the ATRA-induced increase in FOXO1 expression was dependent on QKI-mediated post-transcriptional regulation. Consistently, 5-FU, a widely used chemotherapeutic agent, increased FOXO1 expression via inhibition of QKI. In summary, our study provides initial evidence demonstrating that QKI-mediated repression of FOXO1 may be one of the factors contributing to the oncogenesis and progression of breast carcinoma, which suggests that targeting QKI may serve as a novel strategy to sensitize breast cancers to chemotherapy.

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“…Research has demonstrated that, in prostate cancer cells, CDK1 phosphorylates FOXO1 at Ser249, thereby, inhibiting the transcriptional activity of FOXO1 and reducing the effects of FOXO1 on mitosis. FOXO1 phosphorylation induced by CDK1 not only eliminates the effect of FOXO1 on cell death, but also reduces the inhibitory effects of FOXO1 on the proliferation of malignant transformed cells (53). In addition to CDK1 and CDK2, a recent study suggested that the CDK5 can influence the transcriptional activity of FOXO1 directly.…”

Section: Cyclin-dependent Kinases (Cdks)mentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor

Cited by 142 publications

References 56 publications

Differential Response of Glioma Cells to FOXO1-Directed Therapy

Differential Response of Glioma Cells to FOXO1-Directed Therapy

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

Post-translational modifications of FOXO family proteins

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