p53 is a general repressor of RNA polymerase III transcription

Cairns, Carol

doi:10.1093/emboj/17.11.3112

Cited by 175 publications

(162 citation statements)

References 65 publications

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“…A direct protein-protein interaction between p53 and SL1 prevents the association of SL1 with upstream binding factor, thereby inhibiting the initiation of PolI transcription (Zhai and Comai, 2000). In addition to PolI inhibition, p53 has been reported to be a general repressor of RNA PolIII (Chesnokov et al, 1996;Cairns and White, 1998). By binding to TBP, a TATA-binding protein of the RNA PolIII cofactor TFIIIB complex, p53 blocks TFIIIB recruitment to PolIII-dependent promoters to inhibit transcription initiation (Crighton et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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Section: Discussionmentioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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“…In addition, p53 has been known to function as a repressor of RNA polymerase III transcription and inhibits the synthesis of essential small RNAs including tRNAs (34). Therefore, AIMP2 may control tRNA synthesis in coordination with p53 activation, although its role in the regulation of translation requires further investigation.…”

Section: Discussionmentioning

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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“…As demonstrated here, p70S6k activity is impaired in cells containing active p53. This suggests that p53 may inhibit ribosomal biogenesis via the translational repression of ribosomal protein mRNAs, as well as by other mechanisms such as inhibition of RNA polymerase I activity (Cairns and White, 1998;Budde and Grummt, 1999). These results provide further evidence that the production of new ribosomes, a process necessary for cell cycle progression (Terada et al, 1995;Volarevic et al, 2000) is a target for regulation by p53.…”

Section: Discussionmentioning

confidence: 99%

“…Primarily, p53 functions as a transcription factor controlling expression of genes that affect the cell cycle, induce DNA repair or regulate apoptosis (Arrowsmith, 1999;Kaelin, 1999;Vousden, 2000). It also regulates the activity of RNA polymerases I and III, which transcribe rRNA and tRNA respectively, potentially affecting the synthesis of components of the translational apparatus (Chesnekov et al, 1996;Cairns and White, 1998;Budde and Grummt, 1999;Zhai and Comai, 2000). Furthermore, p53 can associate with ribosomes (Fontoura et al, 1997) and affect the translation of several mRNAs, including those encoding p21 waf1 , cdk4 and fibroblast growth factor-2, as well as p53 itself (Fu et al, 1996;Gorospe et al, 1998;Miller et al, 2000;Galy et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation

et al. 2002

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p53 is an important regulator of cell cycle progression and apoptosis, and inactivation of p53 is associated with tumorigenesis. Although p53 exerts many of its effects through regulation of transcription, this protein is also found in association with ribosomes and several mRNAs have been identified that are translationally controlled in a p53-dependent manner. We have utilized murine erythroleukemic cells that express a temperature-sensitive p53 protein to determine whether p53 also functions at the level of translation. The data presented here demonstrate that p53 causes a rapid decrease in translation initiation. Analysis of several potential mechanisms for regulating protein synthesis shows that p53 has selective effects on the phosphorylation of the eIF4E-binding protein, 4E-BP1, and the activity of the p70 ribosomal protein S6 kinase. These data provide evidence that modulation of translational activity constitutes a further mechanism by which the growth inhibitory effects of p53 may be mediated.

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p53 is a general repressor of RNA polymerase III transcription

Cited by 175 publications

References 65 publications

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

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

p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation

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