Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7

Yada, Masayoshi; Hatakeyama, Susumi; Kamura, Takumi; Nishiyama, Masaaki; Tsunematsu, Ryosuke; Imaki, Hiroyuki; Ishida, Noriko; Okumura, Fumihiro; Nakayama, Keiko; Nakayama, Keiichi I.

doi:10.1038/sj.emboj.7600217

Cited by 712 publications

(738 citation statements)

References 50 publications

(103 reference statements)

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“…A fraction of active GSK-3 trafficks to the nucleus where it colocalizes with c-Myc, consistent with its role in phosphorylating c-Myc and regulating its stability (Gregory et al, 2003). Once phosphorylated at T58 by GSK3, c-Myc is recognized by Fbw7, a component of the SCF(Fbw7) ubiquitin ligase that is responsible for directing proteasome-mediated degradation (Welcker et al, 2004a, b;Yada et al, 2004). Upstream of c-Myc there remains a major gap in knowledge about the mechanisms that support accumulation of active GSK-3 in the nucleus.…”

Section: Introductionmentioning

confidence: 82%

RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3

2005

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The small GTPase RhoB suppresses cancer in part by limiting cell proliferation. However, the mechanisms it uses to achieve this are poorly understood. Recent studies link RhoB to trafficking of Akt, which through its regulation of glycogen synthase kinase-3 (GSK-3) has an important role in controlling the stability of the c-Myc oncoprotein. c-Myc stabilization may be a root feature of human tumorigenesis as it phenocopies an essential contribution of SV40 small T antigen in human cell transformation. In this study we show that RhoB directs efficient turnover of c-Myc in established or transformed mouse fibroblasts and that the attenuation of RhoB which occurs commonly in human cancer is a sufficient cause to elevate c-Myc levels. Increased levels of c-Myc elicited by RhoB deletion increased the proliferation of nullizygous cells, whereas restoring RhoB in null cells decreased the stability of c-Myc and restrained cell proliferation. Mechanistic analyses indicated that RhoB facilitated nuclear accumulation of GSK-3 and GSK-3-mediated phosphorylation of c-Myc T58, the critical site for ubiquitination and degradation of c-Myc. RhoB deletion restricted nuclear localization of GSK-3, reduced T58 phosphorylation, and stabilized c-Myc. These effects were not associated with changes in phosphorylation or localization of Akt, however, differences were observed in phosphorylation and localization of the GSK-3 regulatory Akt-related kinase, serum-and glucocorticoid-inducible protein kinase (SGK). The ability of RhoB to support GSK-3-dependent turnover of c-Myc offers a mechanism by which RhoB acts to limit the proliferation of neoplastically transformed cells.

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Section: Introductionmentioning

confidence: 82%

RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3

2005

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“…This finding explains the frequently elevated expression of cyclin E in breast tumors lacking active Fbw7 (Ekholm-Reed et al, 2004). Other substrates include the oncoproteins c-Myc (Moberg et al, 2004;Welcker et al, 2004;Yada et al, 2004), c-Jun (Nateri et al, 2004;Wei et al, 2005) and Notch (Gupta-Rossi et al, 2001;Oberg et al, 2001;Wu et al, 2001), all of which act to increase cell volume, proliferation and de-differentiation. In addition, Aurora A kinase, an important regulator of mitosis that is frequently overexpressed in human cancer tissues, also serves as a substrate of Fbw7 (Mao et al, 2004;Fujii et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

et al. 2008

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Fbw7 is a tumor suppressor that is mutated in numerous cancers. It encodes an E3 ubiquitin ligase, whose ability to decrease the levels of pivotal regulators of cell growth and proliferation underlies its tumor suppressor function. Here, we explore the consequences of Fbw7 inactivation on the outcome of chemotherapeutic treatments. When exposed to spindle toxins such as vinblastine and taxol, Fbw7-deficient cells undergo extensive mitotic slippage and endoreduplication, rendering them polyploid. A combined deregulation of several Fbw7 target proteins is required for this phenotype. Specifically, elevated expression of cyclin E and Aurora A in Fbw7-deficient cells is required for drug-induced polyploidy. However, overexpression of either cyclin E or Aurora A alone is not sufficient for drug-induced polyploidy. In addition, we demonstrate that Fbw7 deficiency limits the ability of p53 to respond to mitotic toxins but not to DNA damage. Furthermore, Fbw7 expression regulates the p53-dependent induction of genes such as Lats2 and p21 in response to vinblastine. Hence, we suggest that Fbw7 serves as a master regulator of the mitotic and tetraploidy checkpoints.

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“…20 Several E3 ligases, including FBW7, SKP2, TRUSS, HectH9, β-Trcp1 and Hsc70-interacting protein (CHIP), have been identified as responsible for c-Myc degradation. 19,[22][23][24][25][26][27][28] However, it is still unclear whether c-Myc stability is regulated by ubiquitin-independent pathways. In the present study, we demonstrated that proteasome activator REGγ is a novel negative regulator of c-Myc and provided evidence that this regulation is evolutionarily conserved.…”

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confidence: 99%

Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

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-Myc is a key transcriptional factor that has a prominent role in cell growth, differentiation and tumor development. Its protein levels are tightly controlled by ubiquitin-proteasome pathway and frequently deregulated in various cancers. Here, we report that the 11S proteasomal activator REGγ is a novel regulator of c-Myc abundance in cells. We showed that overexpression of wild-type REGγ, but not inactive mutants including N151Y and G250S, significantly promoted the degradation of c-Myc. Depletion of REGγ markedly increased the protein stability of c-Myc. REGγ interacts with the C-terminal region of c-Myc and regulates c-Myc protein turnover. Functionally, REGγ negatively regulates c-Myc-mediated cell proliferation. Interestingly, depletion of the Drosophila Reg homolog (dReg) in developing wings induced the upregulation of Drosophila Myc, which contributes to cell death. Collectively, these results suggest that REGγ proteasome has a conserved role in the regulation of Myc abundance in both mammalian cells and Drosophila.

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Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7

Cited by 712 publications

References 50 publications

RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3

RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

Regulation of c-Myc protein stability by proteasome activator REGγ

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