p14ARF links the tumour suppressors RB and p53

Bates, Stewart; Phillips, Andrew C.; Clark, Paula A.; Stott, Francesca J.; Peters, Gordon; Ludwig, Robert L.; Vousden, Karen H.

doi:10.1038/25867

Cited by 852 publications

(632 citation statements)

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“…E2F1 has been shown to upregulate Arf expression (Bates et al, 1998) and in response, p14 ARF inhibits E2F1 transcriptional activity in vitro (Eymin et al, 2001). In these transfected cells, p14 ARF expression upon the promoter activity was inhibited (50%).…”

Section: Discussionmentioning

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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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%

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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“…This can occur either directly through the transactivation of an E2F-binding site in the ARF promoter -an effect that can be augmented by oncogenic Ras, or indirectly through the activation of death-associated protein (DAP) kinase. [45][46][47][48] p53 regulation occurs largely at the level of protein stability and in normal unstressed cells, p53 is kept at a low level via a negative feedback loop in which p53 induces the transcription of HDM-2 (MDM2 in mice), which in turn binds to p53 and mediates its degradation. 49,50 E2F-1 can stabilise p53 via the induction of the p14ARF protein, which functions by binding directly to HDM-2 and preventing its degradation of p53.…”

Section: A Role In Cancermentioning

confidence: 99%

Life and death decisions by E2F-1

2003

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Deregulation of the transcription factor E2F-1 is a common event in most human cancers. Paradoxically, E2F-1 has been shown to have the ability to induce both cell cycle progression and programmed cell death, leading potentially to both tumour-promoting as well as tumour-suppressive effects. Although the pathway to cell cycle progression seems straightforward with a number of growth-promoting E2F target genes having been described, the pathways to apoptosis are less well defined and more complex. The discovery that E2F-1 'knockout' mice are highly tumour prone has caused a recent surge in the number of reports relating to programmed cell death. This review focuses on these recent findings, highlighting the way in which they have increased our understanding of E2F-1-induced cell death, as well as indicating the questions that remain. Insight gained as to the role of this intriguing molecule in cancer and its potential for targeted therapy will also be discussed.

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“…INK4a de®cient cells that lack ARF and p16 also immortalize in culture and are transformed after introduction of oncogenic Ras (Serrano et al, 1997). Thus it appears that Myc and Ras target two independent but interconnected pathways; the RB pathway and the p53 pathway, linked by a single gene locus INK4a (Bates et al, 1998;. While overexpression of Myc under low serum induces apoptosis and overexpression of Ras senescence, concordant overexpression results in cellular transformation (Sherr, 1998).…”

Section: Prb Regulationmentioning

confidence: 99%