Tumor Suppressor ARF Degrades B23, a Nucleolar Protein Involved in Ribosome Biogenesis and Cell Proliferation

Itahana, Koji; Bhat, Krishna; Jin, Aiwen; Itahana, Yoko; Hawke, David H.; Kobayashi, Ryûji; Zhang, Yanping

doi:10.1016/s1097-2765(03)00431-3

Cited by 409 publications

(482 citation statements)

References 56 publications

(8 reference statements)

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“…Deregulation of protein synthesis machinery through ribosomes functions or deregulation of ribosome biogenesis itself can contribute to tumorigenesis. Among tumor suppressors that might negatively regulate malignant progression by altering rRNA expression, Arf has been involved in the negative control of rRNA maturation (Itahana et al, 2003;Sugimoto et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…More recently a role for Arf in the control of ribosome biogenesis has been suggested: p19 ARF delays rRNA processing in a mdm2 and p53-independent manner (Sugimoto et al, 2003) and associates in very high molecular weight complexes with NPM/B23, a protein involved in the maturation of preribosomal particles (Bertwistle et al, 2004). The human homologue p14 ARF has been shown to partially colocalize with NPM/B23 in the granular component of the nucleolus and to induce its degradation, resulting in the inhibition of rRNA levels and cell death induction (Lindstrom et al, 2000;Itahana et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

Ayrault¹,

Andrique²,

Fauvin³

et al. 2006

Oncogene

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The nucleolar Arf protein has been shown to regulate cell cycle through both p53-dependent and -independent pathways. In addition to the well-characterized Arf-mdm2-p53 pathway, several partners of Arf have recently been described that could participate in alternative regulation process. Among those is the nucleolar protein B23/NPM, involved in the sequential maturation of rRNA. p19 ARF can interact with B23/NPM in high molecular complexes and partially inhibit the cleavage of the 32S rRNA, whereas the human p14 ARF protein has been shown to participate in the degradation of NPM/B23 by the proteasome. These data led to define Arf as a negative regulator of ribosomal RNA maturation. Our recent finding that the human p14 ARF protein was able to specifically interact with the rRNA promoter in a p53-independent context, led us to analyse in vitro and in vivo the consequences of this interaction. Luciferase assay and pulse-chase experiments demonstrated that the rRNA transcription was strongly reduced upon p14 ARF overexpression. Investigations on potential interactions between p14 ARF and the transcription machinery proteins demonstrated that the upstream binding factor (UBF), required for the initiation of the transcriptional complex, was a new partner of the p14 ARF protein. We next examined the phosphorylation status of UBF as UBF phosphorylation is required to recruit on the promoter factors involved in the transcriptional complex. Upon p14 ARF overexpression, UBF was found hypophosphorylated, thus unable to efficiently recruit the transcription complex. Taken together, these data define a new p53-independent pathway that could regulate cell cycle through the negative control of rRNA transcription.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

Ayrault¹,

Andrique²,

Fauvin³

et al. 2006

Oncogene

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“…Reports of a direct interaction between mammalian ARF and NPM (Itahana et al, 2003;Bertwistle et al, 2004;Brady et (Kim et al, 2003).…”

Section: Binding Of Arf Ch To Nucleophosminmentioning

confidence: 99%

“…A notable example is nucleophosmin (also called NPM, B23, numatrin or NO38), which has been consistently identified in screens for ARF binding proteins in different laboratories, including our own (Itahana et al, 2003;Bertwistle et al, 2004;Brady et al, 2004;Korgaonkar et al, 2005). NPM is an abundant, evolutionarily conserved protein that resides predominantly in the nucleolus and also shuttles between the nucleus and cytoplasm (Grisendi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…The gene is also a target of chromosomal translocations and frameshift mutations in human leukaemia (Grisendi et al, 2006). Although a number of reports have suggested that ARF regulates NPM function (Itahana et al, 2003;Brady et al, 2004;Enomoto et al, 2006), a more logical interpretation for which there is growing support would be that binding to NPM is responsible for the nucleolar accumulation and stability of ARF (Kuo et al, 2004;Korgaonkar et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53

et al. 2007

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The ARF tumour suppressor gene encodes a small highly basic protein whose known functions are largely determined by the amino acids encoded within the first exon. In mammals, the protein incorporates additional residues specified by an alternative reading frame in the second exon of INK4a, but this arrangement does not apply to the chicken homologue. In exploring the intracellular localization of chicken p7 ARF , we found that while the FLAG-and HA-tagged versions localize in the nucleolus, in line with mammalian ARF, the GFP-tagged version is excluded from the nucleolus. Here we show that irrespective of the source or composition of the ARF fusion proteins, versions that accumulate in the nucleolus share the ability to bind to nucleophosmin (NPM). Depletion of NPM with siRNA results in the re-location and destabilization of nucleolar forms of ARF but has little effect on the location or stability of a nucleoplasmic form of ARF. Importantly, knockdown of endogenous NPM does not impair the ability of ARF to bind to MDM2 and stabilize p53. These findings support the view that nucleolar localization determines the stability of ARF but not its primary function.

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Oncogenic Ras mutant causes the hyperactivation of NF‐κB via acceleration of its transcriptional activation

et al. 2019

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It is well established that nuclear factor κB (NF‐κB) acts as one of the most important transcription factors for tumor initiation and progression, as it both protects cells from apoptotic/necrotic signals and accelerates angiogenesis and tumor metastasis, which is mediated via the expression of target genes. However, it has not yet been clarified how oncogenic signals accelerate the activation of NF‐κB. In the current study, we utilized untransformed NIH‐3T3 cells stably harboring a κB‐driven luciferase gene to show that an oncogenic mutant of Ras GTPase augmented TNFα‐induced NF‐κB activation. Notably, enforced expression of cyclin‐dependent kinase inhibitors, such as p27Kip1 and p21Cip1, effectively canceled the accelerated activation of NF‐κB, suggesting that oncogenic Ras‐induced cell cycle progression is essential for the hyperactivation of NF‐κB. Furthermore, we found that Ras (G12V) augmented the transcriptional activation of NF‐κB, and this activation required the p38 MAP kinase. We observed that a downstream kinase of p38 MAP kinase, MSK1, was activated by Ras (G12V) and catalyzed the phosphorylation of p65/RelA at Ser‐276, which is critical for its transcriptional activation. Significantly, phosphorylation of the p65/RelA subunit at Ser‐276 was elevated in patient samples of colorectal cancer harboring oncogenic mutations of the K‐Ras gene, and the expression levels of NF‐κB target genes were drastically enhanced in several cancer tissues. These observations strongly suggest that oncogenic signal‐induced acceleration of NF‐κB activation is caused by activation of the p38 MAP kinase–MSK1 signaling axis and by cell cycle progression in cancer cells.

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Tumor Suppressor ARF Degrades B23, a Nucleolar Protein Involved in Ribosome Biogenesis and Cell Proliferation

Cited by 409 publications

References 56 publications

Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation

Binding to nucleophosmin determines the localization of human and chicken ARF but not its impact on p53

Oncogenic Ras mutant causes the hyperactivation of NF‐κB via acceleration of its transcriptional activation

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