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

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

doi:10.1038/sj.emboj.7600217

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

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

Research output: Contribution to journal › Article › peer-review

633 Citations (Scopus)

Abstract

The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7^-1- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.

Original language	English
Pages (from-to)	2116-2125
Number of pages	10
Journal	EMBO Journal
Volume	23
Issue number	10
DOIs	https://doi.org/10.1038/sj.emboj.7600217
Publication status	Published - 2004 May 19

Keywords

Fbw7
SCF complex
Skp2
Ubiquitin ligase
c-Myc

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/sj.emboj.7600217

Cite this

@article{c1067d046ed94040857fda4c2082fbae,

title = "Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7",

abstract = "The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7-1- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.",

keywords = "Fbw7, SCF complex, Skp2, Ubiquitin ligase, c-Myc",

author = "Masayoshi Yada and Shigetsugu Hatakeyama and Takumi Kamura and Masaaki Nishiyama and Ryosuke Tsunematsu and Hiroyuki Imaki and Noriko Ishida and Fumihiko Okumura and Keiko Nakayama and Nakayama, {Keiichi I.}",

year = "2004",

month = may,

day = "19",

doi = "10.1038/sj.emboj.7600217",

language = "English",

volume = "23",

pages = "2116--2125",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Wiley-Blackwell",

number = "10",

}

TY - JOUR

T1 - Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7

AU - Yada, Masayoshi

AU - Hatakeyama, Shigetsugu

AU - Kamura, Takumi

AU - Nishiyama, Masaaki

AU - Tsunematsu, Ryosuke

AU - Imaki, Hiroyuki

AU - Ishida, Noriko

AU - Okumura, Fumihiko

AU - Nakayama, Keiko

AU - Nakayama, Keiichi I.

PY - 2004/5/19

Y1 - 2004/5/19

N2 - The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7-1- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.

AB - The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7-1- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.

KW - Fbw7

KW - SCF complex

KW - Skp2

KW - Ubiquitin ligase

KW - c-Myc

UR - http://www.scopus.com/inward/record.url?scp=2942614705&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2942614705&partnerID=8YFLogxK

U2 - 10.1038/sj.emboj.7600217

DO - 10.1038/sj.emboj.7600217

M3 - Article

C2 - 15103331

AN - SCOPUS:2942614705

SN - 0261-4189

VL - 23

SP - 2116

EP - 2125

JO - EMBO Journal

JF - EMBO Journal

IS - 10

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this