Direct control of the Forkhead transcription factor AFX by protein kinase B

Kops, Geert J. P. L.; Nd, de Ruiter; Vries-Smits, de; Dr, Powell; Jl, Bos; Bm, Burgering

doi:10.1038/19328

Cited by 1,001 publications

(841 citation statements)

References 28 publications

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“…After PtdIns-3,4,5-P3 binding, Akt translocates to the plasma membrane where key serine/threonine residues are phosphorylated by PDKs (Downward, 1998b). Transfection studies have shown that Akt, after being activated by IGF-I/insulin in this manner, can phosphorylate members of the forkhead family transcription factors (Brunet et al, 1999;Guo et al, 1999;Kops et al, 1999;Nakae et al, 1999;Rena et al, 1999;Tang et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The activated Akt can then phosphorylate substrates such as BAD (Datta et al, 1997) and Caspase 9 (Cardone et al, 1998). Activated Akt also translocates to the nucleus Meier et al, 1997) where, as recently discovered, it can phosphorylate the forkhead family transcription factors (Brunet et al, 1999;Guo et al, 1999;Kops et al, 1999;Nakae et al, 1999;Rena et al, 1999;Tang et al, 1999).…”

Section: Introductionmentioning

confidence: 93%

“…Recent transfection studies have demonstrated the phosphorylation of three forkhead family members by Akt in mammalian cells: FKHRL1 (Brunet et al, 1999) FKHR Tang et al, 1999) and AFX (Kops et al, 1999). Un-phosphorylated forkhead transcription factors reside in the nucleus, where they are bound to insulin response elements in the insulinlike growth factor BP-1, PEPCK and TAT (Durham et al, 1999;Guo et al, 1999) genes, and to the Fas ligand promoter (Brunet et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

et al. 2000

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Akt, when activated by IGF/insulin, can phosphorylate forkhead transcription factors. We undertook this study to determine whether epidermal growth factor (EGF) treatment could produce a signaling cascade resulting in phosphorylation of the forkhead transcription factor FKHR in a breast cancer cell line, MDA-MB-231. After establishing ErbB1, cbl, PI3 kinase and Akt were activated in EGF treated MDA-MB-231, we determined by immunoblot with FKHR antiserum that the electrophoretic mobility of FKHR was retarded after EGF treatment. This mobility retardation was reversible by treatment with alkaline phosphatase, and immunoblot with phospho-Ser 256 FKHR antibody further con®rmed phosphorylation on an Akt consensus site after EGF treatment. EGF stimulated FKHR phosphorylation was blocked by the PI3 kinase inhibitor LY294002, and the ErbB1 inhibitor AG1478. FKHR immunoblotting after puri®cation of nuclear and cytoplasmic proteins showed that EGF induced a simultaneous increase of FKHR in the cytoplasm and decrease in the nucleus. This ®nding was con®rmed by immuno¯uorescence staining. Treatment of cells with pharmacological inhibitors of PI3 kinase or ErbB1 blocked this e ect. Thus, these results demonstrate the phosphorylation and nuclear exclusion of FKHR after EGF treatment by a PI3 kinase dependent mechanism, and represent the ®rst report of growth factor regulation of endogenous FKHR localization Oncogene (2000) 19, 4574 ± 4581.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

et al. 2000

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“…FOXOs are extensively regulated by post-translational modifications, including phosphorylation, acetylation and ubiquitination (Obsil and Obsilova, 2008). For example, insulin induces the phosphorylation of FOXO1, FOXO3 and FOXO4 through Akt/protein kinase B, leading to the exclusion of FOXO from the nucleus and the inhibition of FOXO transcription activities (Biggs et al, 1999;Brunet et al, 1999;Kops et al, 1999;Rena et al, 1999;Takaishi et al, 1999). On the other hand, in response to stress, MST1 (Lehtinen et al, 2006) and JNK1 (Essers et al, 2004) phosphorylate FOXO factors at different sites, resulting in nuclear translocation and transactivation.…”

Section: Introductionmentioning

confidence: 99%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the e-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuininduced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.

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“…10 Activated Akt phosphorylates and inhibits several proapoptotic proteins, such as Bad, caspase-9 and the Forkhead transcription factors that include FKHRL1, FKHR and AFX, leading to cell survival. [11][12][13][14][15] Although several growth factors (such as IGF-I, TGF, EPO, PDGF) [16][17][18][19] have been found to induce FKHRL1 phosphorylation via the Akt pathway, the role of Akt in BDNF regulation of FKHRL1 has not been explored. Forkhead transcription factor-induced cell death appears to be mediated by transcriptional regulation of a number of genes including Fas ligand (Fasl) 15,20 and Bim, a BH3 only domain protein that modulates the intrinsic mitochondrial death pathway.…”

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confidence: 99%

Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death

Zhang

et al. 2006

Cell Death Differ

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Chemoresistance and increased expression of TrkB and brain-derived neurotrophic factor (BDNF) are biomarkers of poor prognosis in tumors from patients with neuroblastoma (NB). Previously, we found BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin-induced cell death. In this study, the role of Bim, a proapoptotic protein, was investigated. Bim was involved in paclitaxel but not etoposide or cisplatin-induced cell death in NB cells. Pharmacological and genetic studies showed that BDNF-induced decreases in Bim were regulated by MAPK and not PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death. These data indicate that different chemotherapeutic drugs induce distinct death pathways and growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells.

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Direct control of the Forkhead transcription factor AFX by protein kinase B

Cited by 1,001 publications

References 28 publications

Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

Phosphorylation and nuclear exclusion of the forkhead transcription factor FKHR after epidermal growth factor treatment in human breast cancer cells

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death

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