Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels

Arabi, Azadeh; Rustum, Cecilia; Hallberg, Einar; Wright, Anthony P. H.

doi:10.1242/jcs.00370

Cited by 86 publications

(79 citation statements)

References 49 publications

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“…There is the possibility that the effects of NPM on ribosomal biogenesis and other cellular processes are also influenced by interaction with c-Myc, because c-Myc has been shown to stimulate many cellular functions, including ribosomal biogenesis (2). c-Myc has also been found in the nucleolus under certain conditions (21,22), raising the possibility that they may cooperate in nucleolar functions.…”

Section: Discussionmentioning

confidence: 99%

Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation

Boone

Hann

2008

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

105

117

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The transcription factor c-Myc is essential for cellular proliferation and is one of the most frequently activated oncogenes, but the molecular mechanism mediating its critical role in transformation is unclear. Like c-Myc, multifunctional nucleophosmin (NPM) is tightly regulated during proliferation and is overexpressed in several different types of cancer. Overexpression of NPM enhances proliferation and oncogenemediated transformation, but the mechanism mediating these effects is unknown. We examined whether NPM stimulates proliferation and transformation by affecting c-Myc. Here, we show that NPM is essential for the activities of oncogenic c-Myc and that overexpressed NPM dramatically stimulates c-Myc-induced hyperproliferation and transformation. Endogenous and exogenous NPM directly interact with c-Myc and regulate the expression of endogenous c-Myc target genes at the promoter. Therefore, NPM is a key cofactor for the transforming activity of c-Myc and the interaction with c-Myc may mediate the enhancement of proliferation and transformation induced by NPM overexppression.

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Section: Discussionmentioning

confidence: 99%

Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation

Boone

Hann

2008

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

105

117

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“…There is growing evidence that compartmentalization of nuclear proteins plays an important role in controlling key functions, including gene expression (34), ubiquitination (35), and protein degradation (36). The nuclear distribution pattern of c-Jun in the control cells resembles that of overexpressed transcription factor c-Myc, which is thought to be sequestered to the nucleolus for ubiquitination (37) and degradation by the proteasome (38). In HeLa cells, similar c-Jun-enriched inclusions have been shown to contain aggregates of poyubiquitinated protein and to co-localize with 20 S proteasomes (30), suggesting these structures are sites of protein degradation.…”

Section: Discussionmentioning

confidence: 99%

The 19 S Proteasomal Subunit POH1 Contributes to the Regulation of c-Jun Ubiquitination, Stability, and Subcellular Localization

Nabhan

Ribeiro

2006

Journal of Biological Chemistry

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The AP1 (activator protein 1) transcription factor, c-Jun, is an important regulator of cell proliferation, differentiation, survival, and death. Its activity is regulated both at the level of transcription and post-translationally through phosphorylation, sumoylation, and targeted degradation. The degradation of c-Jun by the ubiquitin proteasome pathway has been well established. Here, we report that POH1, a subunit of the 19 S proteasome lid with a recently described deubiquitinase activity, is a regulator of c-Jun. Ectopic expression of POH1 in HEK293 cells decreased the level of c-Jun ubiquitination, leading to significant accumulation of the protein and a corresponding increase in AP1-mediated gene expression. The stabilization also correlated with a redistribution of c-Jun in the nucleus. These effects were reduced by mutation of a cysteine residue in the Mpr1 pad1 N-terminal plus motif of POH1 (Cys-120) and appeared to be selective for c-Jun, because POH1 had no effect on other proteasomal substrates. Our results identify a novel mechanism of c-Jun regulation in mammalian cells.The 26 S proteasome is the principal site of controlled protein degradation in eukaryotic cells. The 2-to 2.5-MDa proteasome complex consists of a central core (20 S proteasome) and one or two multiprotein regulatory particles (RPs 2 ; 19 S proteasome), which are further organized into base and lid regions (1). The 19 S RP mediates the binding, deubiquitination, and unfolding of substrates into the 20 S core, where proteolysis takes place (2). One of the many cellular proteins targeted for degradation by the proteasome is the AP1 transcription factor, c-Jun (3). In addition to being the most potent transcriptional activator of its group, c-Jun is involved in a myriad of cellular activities, including tumorigenesis (4). Tight control of intracellular concentrations of active c-Jun is therefore required, a process that is achieved through rapid turnover by ubiquitination and degradation. Novel mechanisms for targeted ubiquitination of c-Jun were recently shown to be carried out by c-Jun-specific ubiquitin ligases, such as Itch (5) and SCF Fbw7 (6). Whereas much continues to be learned about mechanisms of c-Jun ubiquitination, little is known about the process of deubiquitination and its contribution to the overall regulation of c-Jun. Cellular deubiquitinases (DUBs) play an important role in controlled protein degradation (7); when bound to the proteasome they mediate the removal of ubiquitin chains as the substrate is being degraded, a step that facilitates substrate translocation into the 20 S chamber and allows for recycling of ubiquitin in the cell. DUBs also provide ubiquitin-editing activity, which can rescue particular substrates from being degraded by removing or trimming the degradation signal. A wide range of DUBs has been identified in eukaryotic cells, including enzymes with specificities for particular ubiquitinated substrates (8) but no specific c-Jun deubiquitinase activity has yet been reported.A number of studies hav...

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“…Nucleolar sequestration has been reported to regulate protein activity (Tao and Levine, 1999;Visintin et al, 1999) One possibility is that PRIMA-1 MET affects ribosomal biogenesis by inducing accumulation of mutant p53 and other proteins in the nucleoli. Studies by Arabi et al (2003Arabi et al ( , 2005, have shown that excess c-Myc can accumulate within nucleoli and activate Pol I transcription in the absence of Pol II transcription, suggesting that c-Myc drives cell growth by stimulating ribosome biogenesis. In contrast, wild-type p53 can suppress Pol I transcription by directly interfering with the assembly of a protein complex that is essential for transcriptional initiation on the rRNA promoter (Zhai and Comai, 2000).…”

Section: Discussionmentioning

confidence: 99%

PRIMA-1MET induces nucleolar accumulation of mutant p53 and PML nuclear body-associated proteins

et al. 2006

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We have previously identified PRIMA-1, a low molecular weight compound that restores the transcriptional transactivation function to mutant p53 and induction of apoptosis. To explore the molecular mechanism for PRIMA-1-induced mutant p53-dependent apoptosis, we examined the intracellular distribution of mutant p53 upon treatment with PRIMA-1 MET by immunofluorescence staining. We found that PRIMA-1 MET induced nucleolar translocation of mutant p53 and the promyelocytic leukemia (PML) nuclear body-associated proteins PML, CBP and Hsp70. Levels of Hsp70 were significantly enhanced by PRIMA-1 MET treatment. PRIMA-Dead, a compound structurally related to PRIMA-1 but unable to induce mutant p53-dependent apoptosis, failed to induce nucleolar translocation of mutant p53. Our results suggest that redistribution of mutant p53 to nucleoli plays a role in PRIMA-1-induced apoptosis. Oncogene (2007) 26, 982-992.

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Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels

Cited by 86 publications

References 49 publications

Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation

Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation

The 19 S Proteasomal Subunit POH1 Contributes to the Regulation of c-Jun Ubiquitination, Stability, and Subcellular Localization

PRIMA-1MET induces nucleolar accumulation of mutant p53 and PML nuclear body-associated proteins

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