Regulation of nucleolar signalling to p53 through NEDDylation of L11

Sundqvist, Anders; Liu, Geng; Mirsaliotis, Antonis; Xirodimas, Dimitris P.

doi:10.1038/embor.2009.178

Cited by 119 publications

(128 citation statements)

References 20 publications

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“…However, the additional regulation of p53 ubiquitination by NUB1 may provide a differential signal, which will determine the subcellular localization of p53 (subnuclear by Tip60 or cytoplasmic by NUB1). These observations, along with recent studies showing that the nucleolar localization of the L11 ribosomal protein is controlled by NEDD8 (Sundqvist et al, 2009), support a diverse role for NEDD8 in controlling protein localization.…”

Section: Discussionsupporting

confidence: 69%

“…The method described in Lee et al (1994) and Sundqvist et al (2009) was used. In brief, cell pellets were resuspended in 1 packed cell volume of Buffer A (10 mM HEPES, pH 8.0, 10 mM KCl, 1.5 mM MgCl 2 , 1mM dithiothreitol, 0.5 mM phenylmethylsulphonyl fluoride) and allowed to swell on ice for 15 min, before being lysed through a 26-gauge needle (five strokes).…”

Section: Subcellular Fractionationmentioning

confidence: 99%

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NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

Liu

Xirodimas

2010

Oncogene

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Non-covalent recognition of ubiquitin (Ub) and ubiquitinlike molecules (Ubls) by interacting proteins has an important role in the regulation of protein function and initiation of signalling events. In addition, growing evidence suggests that regulation of p53 subcellular localization contributes to the biological outcome of the p53 response. Cytoplasmic p53 is shown to promote apoptosis and inhibit the induction of autophagy. In this study we show that NEDD8 ultimate buster 1 (NUB1), a non-covalent interactor of the Ubl NEDD8 (neural precursor cell expressed, developmentally downregulated 8), controls the localization of p53. Expression of NUB1 leads to decreased modification of p53 with NEDD8 and stimulation of p53 ubiquitination. The biological outcome is the cytoplasmic localization and inhibition of the transcriptional activity of p53. Although the effects of NUB1 on p53 depend on NEDDylation and the murine double minute 2 (Mdm2) E3-ligase, the cooperation of NEDD8 with ubiquitin is required. The data identify a role for NEDD8 in controlling p53 localization and suggest that NEDD8 can control protein function through its non-covalent recognition by interacting proteins.

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Section: Discussionsupporting

confidence: 69%

Section: Subcellular Fractionationmentioning

confidence: 99%

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

Liu

Xirodimas

2010

Oncogene

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“…A surplus of free ribosomal proteins induced by ribosomal stress promotes their interaction with Mdm2 in the nucleoplasm. In case of rpL11, its neddylation has a role in necleolar p53 signaling in response to perturbation of ribosomal biogenesis (Sundqvist et al, 2009). Ribosomal protein L11, L5, L23 and S7 have all been shown to bind the central domain of Mdm2 in response to ribosomal stress (Zhang and Lu, 2009).…”

Section: Introductionmentioning

confidence: 99%

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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“…The attachment of Rub1 (rubylation) to cullin proteins and the subsequent regulation of a multi-subunit E3 ligase, the Skp, cullin, and F-box containing complex, is probably the most prevalent, and clearly the best studied, biological function reported so far (22,23,27,28). However, some other proteins have recently been shown to be modified by Nedd8, including p53 and its E3 ligase Mdm2 (29 -31), p73 (a homolog of p53) (32), ribosomal protein L11 (33,34), epidermal growth factor receptor (EGFR) (35), caspase-7 (36,37), and parkin (38,39), though the effects are still vague, particularly as the ratio of modified to unmodified forms of each protein is extremely low. Complicating matters, many of these proteins are also reported to be targets for ubiquitination, and in many cases the same E3 enzymes are required for both ubiquitination and rubylation.…”

mentioning

confidence: 99%

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

Singh

Zerath

Kleifeld

et al. 2012

Molecular & Cellular Proteomics

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Of all ubiquitin-like proteins, Rub1 (Nedd8 in mammals) is the closest kin of ubiquitin. We show via NMR that structurally, Rub1 and ubiquitin are fundamentally similar as well. Despite these profound similarities, the prevalence of Rub1/Nedd8 and of ubiquitin as modifiers of the proteome is starkly different, and their attachments to specific substrates perform different functions. Recently, some proteins, including p53, p73, EGFR, caspase-7, and Parkin, have been shown to be modified by both Rub1/ Nedd8 and ubiquitin within cells. To understand whether and how it might be possible to distinguish among the same target protein modified by Rub1 or ubiquitin or both, we examined whether ubiquitin receptors can differentiate between Rub1 and ubiquitin. Surprisingly, Rub1 interacts with proteasome ubiquitin-shuttle proteins comparably to ubiquitin but binds more weakly to a proteasomal ubiquitin receptor Rpn10. We identified Rub1-ubiquitin heteromers in yeast and Nedd8-Ub heteromers in human cells. We validate that in human cells and in vitro, human Rub1 (Nedd8) forms chains with ubiquitin where it acts as a chain terminator. Interestingly, enzymatically assembled K48-linked Rub1-ubiquitin heterodimers are recognized by various proteasomal ubiquitin shuttles and receptors comparably to K48-linked ubiquitin homodimers. Furthermore, these heterologous chains are cleaved by COP9 signalosome or 26S proteasome. A derubylation function of the proteasome expands the repertoire of its enzymatic activities. In contrast, Rub1 conjugates may be somewhat resilient to the actions of other canonical deubiquitinating enzymes. Taken together, these findings suggest that once Rub1/Nedd8 is channeled into ubiquitin pathways, it is recognized essentially like The selective degradation of many proteins in eukaryotic cells is a highly specific and irreversible process required to perform vital cellular functions such as cell cycle progression (1, 2), differentiation and development (3, 4), and transcriptional control (5). One of the major pathways involved in this selective degradation is the ubiquitin-proteasome pathway. In this pathway, ubiquitin (Ub), a 76-amino-acid protein, is attached to the substrate, and this is followed by the recognition and degradation of the substrate by a protein complex collectively known as proteasome (6 -8).The attachment of Ub (ubiquitination) to a substrate protein is achieved via a cascade of enzymatic reactions (involving E1, E2, and E3 enzymes) that results in the formation of an isopeptide bond between the C-terminal glycine of Ub and a lysine residue of the substrate (9 -11). Sequential repetition of this cascade can result in the attachment of a chain of Ub molecules (polyubiquitin) to the substrate protein. The length and topology of the polyubiquitin (polyUb) tag decide the fate of the substrate protein. For example, we and others have shown that a K48-linked tetraubiquitin (tetraUb) chain that acts as a proteasomal degradation signal forms a "closed" structure (12, 13), whereas a K63-linked Ub...

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Regulation of nucleolar signalling to p53 through NEDDylation of L11

Cited by 119 publications

References 20 publications

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

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

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

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