An ARF-Independent c-MYC-Activated Tumor Suppression Pathway Mediated by Ribosomal Protein-Mdm2 Interaction

Macías, Everardo; Jin, Aiwen; Deisenroth, Chad; Bhat, Krishna; Mao, Hua; Lindström, Mikael S.; Zhang, Yanping

doi:10.1016/j.ccr.2010.08.007

Cited by 192 publications

(275 citation statements)

References 55 publications

(81 reference statements)

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“…But, contrary to our expectation, the p53 level was not decreased. This result is consistent with the recent data showing that p14 ARFindependent p53 pathway exists in ribosomal stress condition (Macias et al, 2010).…”

Section: Discussionsupporting

confidence: 94%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

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Section: Discussionsupporting

confidence: 94%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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“…The data in C. elegans recapitulate the results in the transgenic Mdm2C305F mice where p53 is insensitive to nucleolar stress induced by ActD, but not to other forms of DNA damage, due to lack of Mdm2-RP binding 44 . Therefore, lack of nucleolar stress signaling to CEP-1/p53 in C. elegans may be due to the absence of Mdm2.…”

supporting

confidence: 74%

“…Both compounds inhibit RPL11-NEDDylation and reduce the mobility of RPL11 in the nucleolus. Furthermore, the p53 activation induced by either compound depends on the interaction of RPL11/RPL5 with Mdm2, which is regarded as a key step in p53 activation specifically upon nucleolar stress and not upon DNA damage 44 . Therefore, despite the pleiotropic effects induced due to inhibition of CRL function, p53 activation by MLN4924 depends strictly on the RP-Mdm2 module.…”

Section: Discussionmentioning

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.

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“…We focused on RPL5 and RPL11, in this study, as they can regulate the MDM2-p53 loop in both in vitro and in vivo model systems. [30][31][32][33] The interaction of RPL5 or RPL11 with TAp73 was further verified using an anti-GFP antibody for the inverse co-IP assay (Figure 1b). Surprisingly, the RPL5-or RPL11-TAp73 interaction was MDM2-independent as ectopic TAp73 was also co-immunoprecipitated with ectopic RPL5 or RPL11 in MEF MDM2 − / − /p53 − / − cells (Figure 1c).…”

Section: Rpl11 and Rpl5 Bind To N-terminal Domain Of Tap73mentioning

confidence: 81%

Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

et al. 2014

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Over the past decade, a number of ribosomal proteins (RPs) have been found to have a role in activating the tumor suppressor p53 by directly binding to MDM2 and impeding its activity toward p53. Herein, we report that RPL5 and RPL11 can also enhance the transcriptional activity of a p53 homolog TAp73, but through a distinct mechanism. Interestingly, even though RPL5 and RPL11 were not shown to bind to p53, they were able to directly associate with the transactivation domain of TAp73 independently of MDM2 in response to RS. This association led to perturbation of the MDM2-TAp73 interaction, consequently preventing MDM2 from its association with TAp73 target gene promoters. Furthermore, ectopic expression of RPL5 or RPL11 markedly induced TAp73 transcriptional activity by antagonizing MDM2 suppression. Conversely, ablation of either of the RPs compromised TAp73 transcriptional activity, as evident by the reduction of p21 and Puma expression, in response to 5-fluorouracil (5-FU). Consistently, overexpression of RPL5 or RPL11 enhanced, but knockdown of either of them hampered, TAp73-mediated apoptosis. Intriguingly, simultaneous knockdown of TAp73 and either of the RPs was required for rescuing the 5-FU-triggered S-phase arrest of p53-null tumor cells. These results demonstrate a novel mechanism underlying the inhibition of tumor cell proliferation and growth by these two RPs via TAp73 activation.

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An ARF-Independent c-MYC-Activated Tumor Suppression Pathway Mediated by Ribosomal Protein-Mdm2 Interaction

Cited by 192 publications

References 55 publications

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

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

Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

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