Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway

Horn, Henning F.; Vousden, Karen H.

doi:10.1038/onc.2008.189

Cited by 125 publications

(140 citation statements)

References 62 publications

(100 reference statements)

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“…Supporting this notion, L5 and L11 synergistically inhibit MDM2, leading to robust activation of p53 compared with overexpression of L5 or L11 individually (34). Additionally, many of these RPs appear to bind to different regions within the central acidic and zinc finger domains of MDM2 (9,18,(21)(22)(23)(24).…”

mentioning

confidence: 70%

Interplay between Ribosomal Protein S27a and MDM2 Protein in p53 Activation in Response to Ribosomal Stress

Sun

DeVine

Challagundla

et al. 2011

Journal of Biological Chemistry

107

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The tumor suppressor protein p53 is stabilized and activated to induce cell cycle arrest or apoptosis in response to diverse stress, including DNA damage and oncogenic stress, thus preventing cell from genomic instability and malignant transformation (1-3). Studies over the past decade have revealed that p53 also plays a crucial role in mediating the cellular response to a newly defined stress called ribosomal stress (4), which is induced by perturbation of ribosomal biogenesis. By doing so, p53 coordinates ribosomal biogenesis (cell growth) with cell cycle progression (cell division). Ribosomal biogenesis includes coordinated synthesis of ribosomal RNA (rRNA) and ribosomal proteins (RPs), 2 rRNA processing, and the assembly of the mature ribosome subunits in the nucleolus and their transport into the cytoplasm (4, 5). Disturbing any one of the steps perturbs ribosomal biogenesis and triggers ribosomal stress (4). Because ribosomal stress is often accompanied by the disruption of nucleolar integrity, it is also referred as to nucleolar stress (6). Examples of ribosomal stress include inhibition of rRNA synthesis by treatment with a low dose of actinomycin D (Act D) (7-9) or mycophenolic acid (MPA) (10), inhibition of rRNA processing by treatment with 5-fluorouracil (5-FU) (11), genetic disruption of the RNA polymerase I transcription initiation factor TIF-IA (12), and knockdown of individual RPs (13-15) or nucleolar factors such as nucleostemin (16).Emerging evidence has established a critical role for a group of RPs, including L5, L11, L23, L26, S7, and S27 (8, 9, 17-24), in mediating p53 signaling in response to ribosomal stress. These RPs, when overexpressed or in response to ribosomal stress, bind to MDM2 and inhibit MDM2-mediated p53 ubiquitination and degradation, leading to stabilization and activation of p53. It is well known that MDM2 forms an elegant feedback regulatory loop with p53, as MDM2 is transcriptionally induced by p53 (25-27), whereas it in turn directly inhibits p53 transcriptional activity (28, 29) and mediates p53 ubiquitination and proteasomal degradation (30, 31). Interestingly, knockdown of certain RPs including L5, L11, and S7 attenuates p53 signaling after ribosomal stress (7-11, 18, 24), indicating that these RPs play a non-redundant role in ribosomal stress-induced p53 activation. Furthermore, mice with a knockin of the cancer-associated MDM2 mutant, C305F (MDM2 C305F ), which fails to bind to L5 and L11 (32), displayed a specific defect in p53 signaling in response to ribosomal stress but not DNA damage, compellingly validating the ribosomal stress-induced RPs-MDM2-p53 signaling pathway in vivo (33).Multiple RPs are required for p53 activation in response to ribosomal stress, suggesting that they may form a multi-RP-MDM2 protein complex to optimally suppress MDM2 function. Supporting this notion, L5 and L11 synergistically inhibit MDM2, leading to robust activation of p53 compared with overexpression of L5 or L11 individually (34). Additionally, many of these RPs appear to bind to ...

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mentioning

confidence: 70%

Interplay between Ribosomal Protein S27a and MDM2 Protein in p53 Activation in Response to Ribosomal Stress

Sun

DeVine

Challagundla

et al. 2011

Journal of Biological Chemistry

107

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“…Interaction of these 2 proteins in a more general context was reported recently, when B23 was implicated in directing the nuclear export of both 40S and 60S ribosomal subunit proteins (42). L5 has also been reported to inhibit MDM2-mediated p53 ubiquitination and degradation, by inhibiting the E3 ubiquitin ligase activity of MDM2 (25,43,44).…”

Section: Discussionmentioning

confidence: 99%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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Mouse mammary tumor virus (MMTV) is associated primarily with mammary carcinomas and lymphomas. The signal peptide of the MMTV envelope precursor is uniquely targeted to nucleoli of cells that harbor the virus, where it can function as a nuclear export factor for intron-containing transcripts. Antibodies to this signal peptide, which we refer to as p14, were previously shown to label nucleoli in a subset of human breast cancers. To look for additional cellular functions of p14, different mutants were ectopically expressed in the MCF-7 human breast cancer cell line. This approach identified motifs responsible for its nucleolar targeting, nucleocytoplasmic shuttling, target protein (B23, nucleophosmin) binding, and phosphorylation at serine 18 and 65 both in situ and in vitro. To test the role of these phosphorylation sites, we carried out in vivo tumorigenesis studies in severe combined immunodeficient mice. The findings show that the p14-Ser65Ala mutation is associated with impaired tumorigenicity, whereas the p14-Ser18Ala mutation is associated with enhanced tumorigenicity. Microarray analysis suggests that phosphorylation at serine 18 or at serine 65 is associated with transcriptional regulation of the L5 nucleolar ribosomal protein (a p14 target) and the Erb-B signal transduction pathway. Taken together, these results show that the phosphorylation status of p14 determines whether it functions as a pro-oncogenic or antioncogenic modulator.

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“…Under these conditions, several RPs have been reported to block Mdm2 E3-ligase activity towards p53 through direct binding to Mdm2. In particular, for RPL11 and RPL5, a cooperation between the 2 RPs and 5S rRNA enhances Mdm2 inhibition under ribosomal stress conditions 26,27 . This causes p53 stabilisation, activation of the p53 response and cell cycle arrest 28, 29, 30 ,31 .…”

Section: Introductionmentioning

confidence: 99%

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

et al. 2015

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The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway Bailly, A.; Perrin, A.; Bou Malhab, L. J.; Pion, E.; Larance, M.; Nagala, M.; Smith, P.; O'Donohue, M.-F.; Gleizes, P.-E.; Zomerdijk, Josephus; Lamond, Angus; Xirodimas, D. P. Published in: Oncogene DOI:10.1038/onc.2015.104 Publication date: 2016 Document VersionPeer reviewed version Link to publication in Discovery Research Portal Citation for published version (APA):Bailly, A., Perrin, A., Bou Malhab, L. J., Pion, E., Larance, M., Nagala, M., ... Xirodimas, D. P. (2016). The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway. Oncogene, 35(4), 415-426. DOI: 10.1038415-426. DOI: 10. /onc.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

show abstract

Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway

Cited by 125 publications

References 62 publications

Interplay between Ribosomal Protein S27a and MDM2 Protein in p53 Activation in Response to Ribosomal Stress

Interplay between Ribosomal Protein S27a and MDM2 Protein in p53 Activation in Response to Ribosomal Stress

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

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