Regulating the p53 system through ubiquitination

Yang, Yili; Li, Chou-Chi H.; Weissman, Allan M.

doi:10.1038/sj.onc.1207411

Cited by 173 publications

(138 citation statements)

References 124 publications

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“…Given that both p53 and PARP-1 are important components in DNA damage checkpoint activation (Huber et al, 2004), our studies strongly suggest that spindle-checkpoint impairment owing to BubR1 deficiency weakens cell's ability to cope with genotoxic stresses. It is known that p53 levels are kept low in the cells through ubiquitylation and proteasomal degradation (Yang et al, 2004). Upon various stresses, p53 is stabilized and activated through diverse pathways that include inhibition of ubiquitylation.…”

Section: Discussionmentioning

confidence: 99%

BubR1 is involved in regulation of DNA damage responses

Fang

Wang

et al. 2006

Oncogene

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Section: Discussionmentioning

confidence: 99%

BubR1 is involved in regulation of DNA damage responses

Fang

Wang

et al. 2006

Oncogene

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“…4D). To confirm this conclusion, we tested which p53 mutation (22)(23)(24) would affect the interaction with AIMP2. Whereas the p53 mutants at 175 and 248 bound to AIMP2, the mutant at 22/23 lost its binding capability (Fig.…”

Section: Aimp2 Controls the P53mentioning

confidence: 99%

AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53

Han¹,

Park²,

Park³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

108

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AIMP2/p38 is a scaffolding protein required for the assembly of the macromolecular tRNA synthetase complex. Here, we describe a previously unknown function for AIMP2 as a positive regulator of p53 in response to genotoxic stresses. Depletion of AIMP2 increased resistance to DNA damage-induced apoptosis, and introduction of AIMP2 into AIMP2-deficient cells restored the susceptibility to apoptosis. Upon DNA damage, AIMP2 was phosphorylated, dissociated from the multi-tRNA synthetase complex, and translocated into the nuclei of cells. AIMP2 directly interacts with p53, thereby preventing MDM2-mediated ubiquitination and degradation of p53. Mutations in AIMP2, affecting its interaction with p53, hampered its ability to activate p53. Nutlin-3 recovered the level of p53 and the susceptibility to UV-induced cell death in AIMP2-deficient cells. This work demonstrates that AIMP2, a component of the translational machinery, functions as proapoptotic factor via p53 in response to DNA damage.A minoacyl-tRNA synthetases (ARSs) are the enzymes that ligate specific amino acids to tRNAs before protein synthesis. In higher eukaryotic systems, nine different ARSs form an intriguing macromolecular complex with three nonenzymatic factors called ARS-interacting, multifunctional proteins (AIMPs) (1, 2). Many of these complex-forming ARSs, as well as AIMPs, play diverse regulatory roles that are not directly related to protein synthesis (2). Among the three AIMPs, AIMP1 is secreted as a cytokine working in immune, angiogenesis, and wound-healing processes (3-7) and also functions as a hormone controlling glucose homeostasis (8). AIMP3 is a tumor suppressor required for chromosome integrity (9, 10). Although AIMP2 is critical for the assembly of the multi-ARS complex (11), it also suppresses cell proliferation via down-regulation of c-Myc (12). In addition, AIMP2 was shown to be involved in Parkinson's disease, inducing neural cell death (13). However, it is yet to be determined how AIMP2 is involved in the control of cell death. In this work, we investigated the functional significance and molecular behavior of AIMP2 during the control of cell death and the relationship of AIMP2 associated with the multi-ARS complex and its proapoptotic activity. Results AIMP2-Deficient Cells AreResistant to Cell Death. To see the importance of AIMP2 during the control of cell death, we subjected 12.5-d AIMP2 ϩ/ϩ and AIMP2 Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) to UV irradiation and compared their apoptotic sensitivity. The apoptotic cells, indicated by the subG1 portion, were increased Ϸ3-fold by UV irradiation in AIMP2 ϩ/ϩ but not in AIMP2 Ϫ/Ϫ cells (Fig. 1A). Transfection of AIMP2 into AIMP2 Ϫ/Ϫ MEFs restored the apoptotic sensitivity to UV irradiation (Fig. 1B). We also compared the apoptotic response of AIMP2 ϩ/ϩ and AIMP2 Ϫ/Ϫ MEFs to UV irradiation by monitoring caspase-3 activation. Procaspase-3 cleavage resulting in caspase-3 generation was observed in AIMP2 ϩ/ϩ but not in AIMP2 Ϫ/Ϫ cells (Fig. 1C). Suppression of AIMP2 via gene-specific siRNA...

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“…After 48 h, the endogenous levels of Jab1 and actin were detected using anti-Jab1 and anti-actin antibodies, respectively. B, H1299 cells pretreated with the control (panels 1-8) or Jab1 siRNA (panels 9 -12) were transfected with the plasmids expressing HA-p53 (panels 1 and 2), Hdm2 (panels 3 and 4), or HA-p53 ϩ Hdm2 (panels [5][6][7][8][9][10][11][12]. The proteins were detected as described in the legend to Fig.…”

Section: Jab1 Induces the Nuclear Exclusion And Degradation Of P53-bementioning

confidence: 99%

Jab1 Induces the Cytoplasmic Localization and Degradation of p53 in Coordination with Hdm2

Lee

Sung

et al. 2006

Journal of Biological Chemistry

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The biological mechanisms for maintaining the basal level of p53 in normal cells require nuclear exclusion and cytoplasmic degradation. Here, we showed that Jab1 facilitates p53 nuclear exclusion and its subsequent degradation in coordination with Hdm2. p53 was excluded from the nucleus in the presence of Jab1; this exclusion was prevented by leptomycin B treatment. Nuclear export of p53 was accompanied by a decrease in the levels of p53, as well as of its target proteins, which include p21 and Bax. Domain analyses of Jab1 showed that the N-terminal domain, 1-110, was capable of inducing cytoplasmic translocation of p53. Furthermore, 110 -191 was required to facilitate the degradation of p53. Neither of these mutants incorporated into the CSN complex, indicating that Jab1 could affect the levels of p53 independent of intact CSN complex. Conversely, Jab1 was incapable of translocating and degrading two p53 mutants, W23S and 6KR, neither of which could be modified by Hdm2. Moreover, Jab1 did not affect the cellular localization or protein levels of p53 in p53 and Hdm2 double-null mouse embryo fibroblasts. We further observed that the ablation of endogenous Jab1 by small interfering RNA prevented Hdm2-mediated p53 nuclear exclusion. Under stressed conditions, which could sequester Hdm2 in its inactive state, Jab1 did not affect p53. Our studies implicate that Jab1 is required to remove post-translationally modified p53 and provide a novel target for p53-related cancer therapies.

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Regulating the p53 system through ubiquitination

Cited by 173 publications

References 124 publications

BubR1 is involved in regulation of DNA damage responses

BubR1 is involved in regulation of DNA damage responses

AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53

Jab1 Induces the Cytoplasmic Localization and Degradation of p53 in Coordination with Hdm2

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