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 journalArticle

475 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 languageEnglish
Pages (from-to)2116-2125
Number of pages10
JournalEMBO Journal
Volume23
Issue number10
DOIs
Publication statusPublished - May 19 2004

Fingerprint

F-Box Proteins
Phosphorylation
Degradation
Ubiquitination
Threonine
Embryonic Stem Cells
RNA Interference
Stem cells
Serine
Transcriptional Activation
RNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Yada, M., Hatakeyama, S., Kamura, T., Nishiyama, M., Tsunematsu, R., Imaki, H., ... Nakayama, K. I. (2004). Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO Journal, 23(10), 2116-2125. https://doi.org/10.1038/sj.emboj.7600217

Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. / Yada, Masayoshi; Hatakeyama, Shigetsugu; Kamura, Takumi; Nishiyama, Masaaki; Tsunematsu, Ryosuke; Imaki, Hiroyuki; Ishida, Noriko; Okumura, Fumihiko; Nakayama, Keiko; Nakayama, Keiichi I.

In: EMBO Journal, Vol. 23, No. 10, 19.05.2004, p. 2116-2125.

Research output: Contribution to journalArticle

Yada, M, Hatakeyama, S, Kamura, T, Nishiyama, M, Tsunematsu, R, Imaki, H, Ishida, N, Okumura, F, Nakayama, K & Nakayama, KI 2004, 'Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7', EMBO Journal, vol. 23, no. 10, pp. 2116-2125. https://doi.org/10.1038/sj.emboj.7600217
Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO Journal. 2004 May 19;23(10):2116-2125. https://doi.org/10.1038/sj.emboj.7600217
Yada, Masayoshi ; Hatakeyama, Shigetsugu ; Kamura, Takumi ; Nishiyama, Masaaki ; Tsunematsu, Ryosuke ; Imaki, Hiroyuki ; Ishida, Noriko ; Okumura, Fumihiko ; Nakayama, Keiko ; Nakayama, Keiichi I. / Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. In: EMBO Journal. 2004 ; Vol. 23, No. 10. pp. 2116-2125.
@article{184cf948790c4434b1acbbf86884ecb3,
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.",
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 = "5",
day = "19",
doi = "10.1038/sj.emboj.7600217",
language = "English",
volume = "23",
pages = "2116--2125",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
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.

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

VL - 23

SP - 2116

EP - 2125

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 10

ER -