Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D

Schmidt, Marc; Mattos, Sylvia Fernandez de; Horst, Armando van der; Klompmaker, Rob; Kops, Geert J. P. L.; Lam, Eric W.‐F.; Burgering, Boudewijn M.T.; Medema, René H.

doi:10.1128/mcb.22.22.7842-7852.2002

Cited by 501 publications

(391 citation statements)

References 51 publications

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“…Both mRNA and protein levels of cyclin D2 are elevated in Pten-null MEFs, and reintroduction of PTEN downregulated the promoter activity of cyclin D2 in Pten À/À MEFs and U87 cells. Our data are consistent with the previous report that an active FoxO3a, an important downstream effector of PTEN, inhibited cyclin D2 in a colon carcinoma cell line (Schmidt et al, 2002). PTEN was also found to reduce cyclin D3 expression in endometrial carcinomas cells (Zhu et al, 2001).…”

Section: Discussionsupporting

confidence: 93%

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Huang

et al. 2006

Oncogene

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PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3b and b-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3b, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3b/b-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.

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Section: Discussionsupporting

confidence: 93%

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Huang

et al. 2006

Oncogene

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“…We then performed cyclin D1 ChIP/promoter construct experiments in breast cancer cells focusing on a locus involved in both FKHR 30 and estradiol 31 regulation. We first assessed the occupancy of this region by both endogenous ERalpha and FKHR in MCF-7 cells.…”

Section: Phosphorylation At Tyrosine 537 Controls the Estradiol-inducmentioning

confidence: 99%

Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells

et al. 2012

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We report that in breast cancer cells, tyrosine phosphorylation of the estradiol receptor alpha (ERalpha) by Src regulates cytoplasmic localization of the receptor and DNA synthesis. Inhibition of Src or use of a peptide mimicking the ERalpha p-Tyr537 sequence abolishes ERalpha tyrosine phosphorylation and traps the receptor in nuclei of estradiol-treated MCF-7 cells. An ERalpha mutant carrying a mutation of Tyr537 to phenylalanine (ER537F) persistently localizes in nuclei of various cell types. In contrast with ERalpha wt, ER537F does not associate with Ran and its interaction with Crm1 is insensitive to estradiol. Thus, independently of estradiol, ER537F is retained in nuclei, where it entangles FKHR-driving cell cycle arrest. Chromatin immunoprecipitation analysis reveals that overexpression of ER537F in breast cancer cells enhances FKHR interaction with cyclin D1 promoter. This mutant also counteracts cell transformation by the activated forms of Src or PI3-K. In conclusion, in addition to regulating receptor localization, ERalpha phosphorylation by Src is required for hormone responsiveness of DNA synthesis in breast cancer cells.

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“…These cyclin D-CDK4/6 holoenzymes are believed to be crucial for driving cells through the restriction point (Matsushime et al, 1992;Bates et al, 1994;Meyerson and Harlow, 1994), a location at late G1 phase after which cells often become independent of growth factors and refractory to inhibitory signals. Overexpression of the constitutively active nuclear form of FoxO1 or FoxO3a has been shown to repress CDK4 activity and induce cell cycle arrest at G1 phase (Ramaswamy et al, 2002;Schmidt et al, 2002). Conversely, ectopic expression of cyclin D1 can partially overcome the FoxO-induced cell cycle arrest, implicating the downregulation of D-type cyclins as a mechanism of FoxO-induced cell cycle inhibition (Ramaswamy et al, 2002).…”

Section: Foxo and The G1/s Phase Transitionmentioning

confidence: 99%

Many forks in the path: cycling with FoxO

2008

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FoxO transcription factors are an evolutionary conserved subfamily of the forkhead transcription factors, characterized by the forkhead DNA-binding domain. FoxO factors regulate a number of cellular processes involved in cell-fate decisions in a cell-type-and environment-specific manner, including metabolism, differentiation, apoptosis and proliferation. A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of the cell cycle. Consequently, the deregulation of FoxO factors is implicated in the development of numerous proliferative diseases, in particular cancer.

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Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D

Cited by 501 publications

References 51 publications

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells

Many forks in the path: cycling with FoxO

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