The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4

被引:63
作者
Welcker, M
Clurman, BE [1 ]
机构
[1] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA
[2] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA
[3] Univ Washington, Sch Med, Dept Med, Seattle, WA 98104 USA
关键词
D O I
10.1074/jbc.M413377200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cell transformation by simian virus 40 (SV40) results mostly from the highly oncogenic activities of the large T antigen ( LT), which corrupts the cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. The most prominent LT targets are the retinoblastoma protein (pRb) and p53. Here we report that LT binds directly to Fbw7, the substrate recognition component of the SCFFbw7 ubiquitin ligase and a human tumor suppressor. LT binding mislocalizes the nucleolar Fbw7gamma isoform to the nucleoplasm. Interestingly, the binding of LT to Fbw7 occurs via a decoy phospho-epitope within the C terminus of LT that closely mimics the consensus Cdc4 phospho-degron found within Fbw7 substrates. We demonstrate that, using this mode of interaction, LT can interfere with Fbw7-driven cyclin E turnover in vivo and causes increased cyclin E-associated kinase activity. Our data suggest that LT competes with cellular proteins for Fbw7 binding in a substrate-like fashion.
引用
收藏
页码:7654 / 7658
页数:5
相关论文
共 48 条
  • [31] Spruck CH, 2002, CANCER RES, V62, P4535
  • [32] Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line
    Strohmaier, H
    Spruck, CH
    Kaiser, P
    Won, KA
    Sangfelt, O
    Reed, SI
    [J]. NATURE, 2001, 413 (6853) : 316 - 322
  • [33] Species-specific elements in the large T-antigen J domain are required for cellular transformation and DNA replication by simian virus 40
    Sullivan, CS
    Tremblay, JD
    Fewell, SW
    Lewis, JA
    Brodsky, JL
    Pipas, JM
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (15) : 5749 - 5757
  • [34] Defective cardiovascular development and elevated cyclin E and notch proteins in mice lacking the Fbw7 F-box protein
    Tetzlaff, MT
    Yu, W
    Li, MM
    Zhang, PM
    Finegold, M
    Mahon, K
    Harper, JW
    Schwartz, RJ
    Elledge, SJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (10) : 3338 - 3345
  • [35] Mouse Fbw7/Sel-10/Cdc4 is required for Notch degradation during vascular development
    Tsunematsu, R
    Nakayama, K
    Oike, Y
    Nishiyama, M
    Ishida, N
    Hatakeyama, S
    Bessho, Y
    Kageyama, R
    Suda, T
    Nakayama, KI
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (10) : 9417 - 9423
  • [36] METABOLIC TURNOVER OF PHOSPHORYLATION SITES IN SIMIAN VIRUS-40 LARGE T-ANTIGEN
    VANROY, F
    FRANSEN, L
    FIERS, W
    [J]. JOURNAL OF VIROLOGY, 1983, 45 (01) : 442 - 446
  • [37] Simian virus 40 in human cancers
    Vilchez, RA
    Kozinetz, CA
    Arrington, AS
    Madden, CR
    Butel, JS
    [J]. AMERICAN JOURNAL OF MEDICINE, 2003, 114 (08) : 675 - 684
  • [38] THE RETINOBLASTOMA PROTEIN AND CELL-CYCLE CONTROL
    WEINBERG, RA
    [J]. CELL, 1995, 81 (03) : 323 - 330
  • [39] A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size
    Welcker, M
    Orian, A
    Grim, JA
    Eisenman, RN
    Clurman, BE
    [J]. CURRENT BIOLOGY, 2004, 14 (20) : 1852 - 1857
  • [40] The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation
    Welcker, M
    Orian, A
    Jin, JP
    Grim, JA
    Harper, JW
    Eisenman, RN
    Clurman, BE
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (24) : 9085 - 9090