Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

Nakamura, Noriaki; Ramaswamy, Shivapriya; Vázquez, Francisca; Signoretti, Sabina; Loda, Massimo; Sellers, William R.

doi:10.1128/mcb.20.23.8969-8982.2000

Cited by 523 publications

(456 citation statements)

References 61 publications

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“…It was reported that FKHRL1 becomes directly phosphorylated by kinases such as Akt, 23,28,38,39 whereas PTEN mediates indirect dephosphorylation of FKHRL1. 40 In conclusion, this study demonstrates that the nuclear overexpression of Cdc25A indirectly mediated the dephosphorylation of threonine 32 of FKHRL1 and promoted apoptosis, whereas the cytoplasmic overexpression of Cdc25A was apoptosis protective.…”

Section: Cdc25a and Apoptosismentioning

confidence: 57%

Subcellular localisation of Cdc25A determines cell fate

et al. 2003

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Cell division cycle 25A (Cdc25A) was shown to colocalise both with nuclear and cytoplasmic proteins. Recently, we have demonstrated that overexpressed Cdc25A promoted the survival of rat 423 cells through indirect activation of PKBprotein kinase B. Using a Cdc25A:ER fusion protein, which can be shuttled from the cytoplasm into the nucleus, the present investigation evidences that the antiapoptotic effect of Cdc25A was restricted to its cytoplasmic localisation in rat 423 cells. In contrast, nuclear Cdc25A overexpression caused dephosphorylation and nuclear retention of the proapoptotic transcription factor Forkhead in rhabdomyosarcoma-like 1 (FKHRL1) in human N.1 ovarian carcinoma cells. This resulted in the increased constitutive expression of the FKHRL1 targets Fas ligand and Bim, and promoted apoptosis. Thus, the Cdc25A oncogene, which was found to be frequently overexpressed in certain human cancers, can increase or decrease the susceptibility to apoptosis depending on the cell-type-specific subcellular distribution.

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Section: Cdc25a and Apoptosismentioning

confidence: 57%

Subcellular localisation of Cdc25A determines cell fate

et al. 2003

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“…However, we found that when both EGFR and ErbB-2 are blocked by using either a combination of trastuzumab plus gefitinib or the dual inhibitor lapatinib, a significant increase in the levels of p27 kip1 mRNA is also observed. This phenomenon was found to be mediated by FKHRL-1, a member of the Forkhead family of transcription factor [43] that is one of the principal regulators of p27 kip1 mRNA expression. FKHRL-1 is also a AKT substrate: AKT inactivates FKHRL1 by phosphorylation that produces a retention of the transcription factor into the cytoplasm [25].…”

Section: Discussionmentioning

confidence: 99%

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

D’Alessio

Luca

Maiello

et al. 2009

Breast Cancer Res Treat

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International audienceTreatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27 mRNA and in the nuclear levels of the p27 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27 expression

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“…It has been reported that FOXO1 is involved in regulating a variety of biological processes, such as cell-cycle control, differentiation, stress response and apoptosis (Arden, 2007;Frescas and Pagano, 2008). It has been demonstrated that FOXO proteins could act as tumor suppressors as evidenced by its transcriptional induction of CDK inhibitors, including p21 Cip1 , p27 Kip1 and p57 kip2 (Nakamura et al, 2000;Seoane et al, 2004;Roeb et al, 2007). Indeed, FOXO1 expression is downregulated in prostate cancer and endometrial adenocarcinomas (Dong et al, 2006;Ward et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, p21 Cip1 and p27 Kip1 mRNAs were significantly elevated in AEG-1 knocked-down MCF-7 and As transcription factor FOXO1 had previously been found to transcriptionally upregulate p27 Kip1 and to induce p21 Cip1 expression by forming transcriptional complexes with SMAD3 and SMAD4 (Dijkers et al, 2000;Nakamura et al, 2000;Seoane et al, 2004), we asked whether the changes of p27 Kip1 and p21 Cip1 levels caused by AEG-1 were mediated through FOXO1 modulation. Interestingly, although real-time RT-PCR analysis revealed that neither AEG-1 overexpression nor its knockdown changed the level of total FOXO1 mRNA (data not shown), phosphorylated FOXO1 was significantly increased in AEG-1-overexpressing breast cancer cells as compared with that in the control cells, as shown by western blotting analysis, and a dramatic reduction of phosphorylation of FOXO1 was observed in AEG-1 knocked down cells (Po0.05; Figure 5A).…”

Section: Aeg-1 Is Essential For Breast Cancer Cell Proliferationmentioning

confidence: 96%

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

et al. 2009

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We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (Po0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27 Kip1 and p21 Cip1 two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer.

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Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

Cited by 523 publications

References 61 publications

Subcellular localisation of Cdc25A determines cell fate

Subcellular localisation of Cdc25A determines cell fate

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

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