Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo

被引:206
|
作者
Francoz, S
Froment, P
Bogaerts, S
De Clercq, S
Maetens, M
Doumont, G
Bellefroid, E
Marine, JC
机构
[1] State Univ Ghent VIB, Lab Mol Canc Biol, B-9052 Ghent, Belgium
[2] Free Univ Brussels, Mol Embryol Lab, B-6041 Gosselies, Belgium
关键词
cre; lox;
D O I
10.1073/pnas.0508476103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The Mdm2 and Mdm4 oncoproteins are key negative regulators of the p53 tumor suppressor. However, their physiological contributions to the regulation of p53 stability and activity remain highly controversial. Here, we combined a p53 knock-in allele, in which p53 is silenced by a transcriptional stop element flanked by loxP sites, with the mdm2- and mdm4-null alleles. This approach allows Cre-mediated conditional p53 expression in tissues in vivo and cells in vitro lacking Mdm2, Mdm4, or both. Using this strategy, we show that Mdm2 and Mdm4 are essential in a nonredundant manner for preventing p53 activity in the same cell type, irrespective of the proliferation/differentiation status of the cells. Although Mdm2 prevents accumulation of the p53 protein, Mdm4 contributes to the overall inhibition of p53 activity independent of Mdm2. We propose a model in which Mdm2 is critical for the regulation of p53 levels and Mdm4 is critical for the fine-tuning of p53 transcriptional activity, both proteins acting synergistically to keep p53 in check.
引用
收藏
页码:3232 / 3237
页数:6
相关论文
共 50 条
  • [1] Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability
    Pant, Vinod
    Xiong, Shunbin
    Iwakuma, Tomoo
    Quintas-Cardama, Alfonso
    Lozano, Guillermina
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (29) : 11995 - 12000
  • [2] The expression of MDM2, MDM4, p53 and p21 in myeloid neoplasms and the effect of MDM2/MDM4 dual inhibitor
    Eskandari, Mohammad
    Shi, Yang
    Liu, John
    Albanese, Joseph
    Goel, Swati
    Verma, Amit
    Wang, Yanhua
    [J]. LEUKEMIA & LYMPHOMA, 2021, 62 (01) : 167 - 175
  • [3] Mdm2 Splice isoforms regulate the p53/Mdm2/Mdm4 regulatory circuit via RING domain-mediated ubiquitination of p53 and Mdm4
    Fan, Chuandong
    Wang, Xinjiang
    [J]. CELL CYCLE, 2017, 16 (07) : 660 - 664
  • [4] Selective and dual action p53/mdm2/mdm4 antagonists
    Wang, Kan
    Doemling, Alexander
    [J]. CANCER RESEARCH, 2009, 69
  • [5] MDM2 and MDM4: p53 regulators as targets in anticancer therapy
    Toledo, Franck
    Wahl, Geoffrey M.
    [J]. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2007, 39 (7-8): : 1476 - 1482
  • [6] Mdm2 and Mdm4 loss regulates distinct p53 activities
    Barboza, Juan A.
    Iwakuma, Tomoo
    Terzian, Tamara
    El-Naggar, Adel K.
    Lozano, Guillermina
    [J]. MOLECULAR CANCER RESEARCH, 2008, 6 (06) : 947 - 954
  • [7] Peptides and peptidomimetics in the p53/MDM2/MDM4 circuitry - a patent review
    Teveroni, Emanuela
    Luca, Rossella
    Pellegrino, Marsha
    Ciolli, Germana
    Pontecorvi, Alfredo
    Moretti, Fabiola
    [J]. EXPERT OPINION ON THERAPEUTIC PATENTS, 2016, 26 (12) : 1417 - 1429
  • [8] Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
    Grier, JD
    Xiong, SB
    Elizondo-Fraire, AC
    Parant, JM
    Lozano, G
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (01) : 192 - 198
  • [9] Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
    Marine, J-C
    Francoz, S.
    Maetens, M.
    Wahl, G.
    Toledo, F.
    Lozano, G.
    [J]. CELL DEATH AND DIFFERENTIATION, 2006, 13 (06): : 927 - 934
  • [10] Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4
    J-C Marine
    S Francoz
    M Maetens
    G Wahl
    F Toledo
    G Lozano
    [J]. Cell Death & Differentiation, 2006, 13 : 927 - 934