A large-scale RNAi screen in human cells identifies new components of the p53 pathway

Berns, Katrien; Hijmans, E. Marielle; Mullenders, Jasper; Brummelkamp, Thijn R.; Velds, Arno; Heimerikx, Mike; Kerkhoven, Ron; Madiredjo, Mandy; Nijkamp, Wouter; Weigelt, Britta; Agami, Reuven; Ge, Wei; Cavet, Guy; Linsley, Peter S.; Beijersbergen, Roderick L.; Bernards, René

doi:10.1038/nature02371

Cited by 992 publications

(764 citation statements)

References 30 publications

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“…Recent data demonstrate that Tip60 is a key component in the antiproliferative cellular response. Indeed, Tip60 is required for p19 ARF / p53-mediated proliferation arrest and plays a critical role in genotoxic signalling networks (Berns et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation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

confidence: 99%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

et al. 2006

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“…In agreement with its function in histone acetylation, Tip60 is mainly involved in transcriptional activation of specific genes (Gaughan et al, 2001;Berns et al, 2004;Legube et al, 2004). Transcriptional regulation of some genes, such as E2F or c-mycdependent genes, most likely involves the whole Tip60 complex (Frank et al, 2003;Taubert et al, 2004).…”

Section: Introductionmentioning

confidence: 88%

The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

et al. 2009

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The Tip60 histone acetyltransferase belongs to a multimolecular complex that contains many chromatin remodeling enzymes including the ATPase p400, a protein involved in nucleosomal incorporation of specific histone variants and that can directly or indirectly repress some Tip60-dependent pathways. Tip60 activity is critical for the cellular response to DNA damage and is affected during cancer progression. Here, we found that the ratio between Tip60 and p400 mRNAs is affected in most colorectal carcinoma. Strikingly, reversing the p400/ Tip60 imbalance by Tip60 overexpression or the use of siRNAs resulted in increased apoptosis and decreased proliferation of colon-cancer-derived cells, suggesting that this ratio defect is important for cancer progression. Furthermore, we demonstrate that the p400/Tip60 ratio controls the oncogene-induced DNA damage response, a known anticancer barrier. Finally, we found that it is also critical for the response to 5-fluorouracil, a first-line treatment against colon cancer. Together, our data indicate that the p400/Tip60 ratio is critical for colon cancer cells proliferation and response to therapeutic drugs through the control of stress-response pathways.

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“…Cell infection with siRNAs b-Catenin siRNA constructs were obtained from a library in which gene-targeting oligonucleotides were cloned downstream to the polymerase III Histone H1-RNA promoter in the pRETROSUPER vector (Berns et al, 2004). Two different oligonucleotide sequences targeting b-catenin gene were verified by sequencing and used in combination to transduce CRC cell lines.…”

Section: Western Immunoblot Analysismentioning

confidence: 99%

A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

et al. 2006

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Overexpressed or activated hepatocyte growth factor receptor, encoded by the MET proto-oncogene, was found in the majority of colorectal carcinomas (CRCs), whose stepwise progression to malignancy requires transcriptional activation of b-catenin. We here demonstrate that a functional crosstalk between Met and b-catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts b-catenin tyrosine phosphorylation and dissociation from Met, and upregulates b-catenin expression via the phosphatidylinositol 3-kinase pathway in conditions that mimic those found by the invading and metastasizing cells. Additionally, a transcriptionally active form of b-catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the b-catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic b-catenin. In the mirror experiments, either Met or b-catenin knocking down also reduces their protein level. In biological assays, b-catenin knocking down abrogates the HGF-induced motile phenotype, whereas active b-catenin fosters ligand-independent cell scattering. Met and b-catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and b-catenin pathways are mutually activated in CRC cells. This might generate a selfamplifying positive feedback loop resulting in the upregulation of the invasive growth properties of CRC cells.

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A large-scale RNAi screen in human cells identifies new components of the p53 pathway

Cited by 992 publications

References 30 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

The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

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