p16INK4A and p19ARF act in overlapping pathways in cellular immortalization

Carnero, Amancio; Hudson, James D.; Price, CJ; Beach, David

doi:10.1038/35004020

Cited by 266 publications

(242 citation statements)

References 31 publications

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“…Consistently, we have obtained some results showing that p14 ARF is unable to induce a cell cycle arrest in RB-deficient SAOS2 cells and that RB knockdown partially prevents p14 ARF -mediated G 2 arrest in our stable inducible clone (data not shown). These data are reminiscent with a previous study showing that p19 ARF normally functions p14 ARF regulates RB acetylation C Leduc et al by regulating both the RB and p53 pathways (Carnero et al, 2000). In addition, we recently demonstrated that p14 ARF and Tip60 cooperate to induce a p53-independent DNA damage checkpoint in response to alkylating agents (Eymin et al, submitted).…”

Section: Discussionsupporting

confidence: 84%

“…Collectively, these observations demonstrate that p14 ARF interferes in a direct or indirect manner with some effectors of the RB signalling pathway to control cell growth. The importance of such relationships is underlined by the fact that in a genetic study in mice, p14 ARF has been reported to functionally activate both the p53 and the RB pathways (Carnero et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

et al. 2006

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p14 ARF is a tumour suppressor which plays a critical role in p53-dependent or -independent cell growth control. Several studies have recently provided evidence that p14 ARF can also interfere either directly or indirectly with some components of the RB signalling pathway to mediate its antiproliferative activity. The aim of this study was to explore the existence of direct relationships between p14 ARF and RB proteins. We show that p14 ARF promotes the accumulation of a hypoacetylated RB protein, when it is upregulated in a model of stable-inducible clones or physiologically induced following cell exposure to cytotoxic agents. Looking for the mechanisms involved in this process, we demonstrate that the histone acetyl transferase Tip60 directly interacts with RB and stimulates its degradation by the proteasome through acetylation of its C-terminus. Furthermore, and consistent with p14 ARFinduced RB accumulation, we provide evidence that p14 ARF prevents Tip60-mediated RB acetylation, therefore precluding its proteasomal degradation. Overall, our results identify a novel mechanism by which p14 ARF controls the RB pathway to trigger its antiproliferative function.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

et al. 2006

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“…More than half of human cancer types present mutations in the TP53 gene (Hollstein et al, 1991), probably because its normal activity would hamper the accumulation of genetic lesions needed for malignant progression (Campbell et al, 2010). Albeit TP53 knockout suffices to immortalize mouse cells (Carnero et al, 2000), no similar outcome has been observed in human cells unless they constitutively express telomerase, possibly owing to the shortness of human telomeres, which limits their lifespan (Hahn and Weinberg, 2002). Nonetheless, it is possible to immortalize primary human prostate epithelial cells by ectopic expression of c-MYC , an oncogene overexpressed in approximately 30% of human cancers (Dang et al, 2008).…”

Section: Early Steps In Carcinogenesis and Metabolismmentioning

confidence: 99%

Metabolic reprogramming of the tumor

2012

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Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution. Implications of this renovated view on some common concepts and in therapeutics are also discussed.

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“…In the absence of p53, Arf still exerts its tumor suppressor function through mechanisms implying other regulators (Carnero et al, 2000;Weber et al, 2000). In this context, p14 ARF has been shown to interact with E2F1 and inhibits its transcriptional activity (Eymin et al, 2001).…”

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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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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p16INK4A and p19ARF act in overlapping pathways in cellular immortalization

Cited by 266 publications

References 31 publications

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

Metabolic reprogramming of the tumor

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

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