p14ARF regulates E2F activity

Mason, Sarah; Loughran, Oonagh; Thangué, Nicholas B. La

doi:10.1038/sj.onc.1205524

Cited by 57 publications

(53 citation statements)

References 47 publications

(82 reference statements)

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“…The E2F transcription factor can activate p14 ARF gene expression and initiate a p53-dependent response (Bates et al, 1998). Furthermore, we and others have demonstrated that p14 ARF associates with E2Fs and its DP1 regulatory partner and regulates their localization and degradation leading to an inactive E2F1 protein (Eymin et al, 2001;Martelli et al, 2001;Datta et al, 2002;Mason et al, 2002). 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.…”

Section: Introductionsupporting

confidence: 52%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation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

confidence: 52%

RETRACTED ARTICLE: p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation

et al. 2006

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“…Nevertheless, a number of follow-up studies clearly demonstrated that this is not entirely the case. In particular, distinct members of E2F family of transcription factors were suggested to be critical downstream targets of p53-independent growth arrest programmes engaged by p14 ARF (Eymin et al, 2001;Martelli et al, 2001;Mason et al, 2002;Rowland et al, 2002). Furthermore, a delay in S-phase progression with consecutive accumulation of cells in G1 phase of the cell cycle upon expression of p14 ARF was shown to occur independently of p53 (Yarbrough et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Loss of p21 disrupts p14ARF-induced G1 cell cycle arrest but augments p14ARF-induced apoptosis in human carcinoma cells

et al. 2005

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The human INK4a locus encodes two structurally unrelated tumor suppressor proteins, p16 INK4a and p14 ARF (p19 ARF in the mouse), which are frequently inactivated in human cancer. Both the proapoptotic and cell cycleregulatory functions of p14 ARF were initially proposed to be strictly dependent on a functional p53/mdm-2 tumor suppressor pathway. However, a number of recent reports have implicated p53-independent mechanisms in the regulation of cell cycle arrest and apoptosis induction by p14 ARF . Here, we show that the G1 cell cycle arrest induced by p14 ARF entirely depends on both p53 and p21 in human HCT116 and DU145 carcinoma cells. In contrast, neither loss of p53 nor p21 impaired apoptosis induction by p14 ARF as evidenced by nuclear DNA fragmentation, phosphatidyl serine exposure, and caspase activation, which included caspase-3/7-and caspase-9-like activities. However, lack of functional p21 resulted in the accumulation of cells in G2/M phase of the cell cycle and markedly enhanced p14 ARF -induced apoptosis that was, nevertheless, efficiently inhibited by the cell permeable broad-spectrum caspase inhibitor zVAD-fmk (valyl-alanylaspartyl-(O)-methyl)-fluoromethylketone). Thus, loss of cell cycle restriction point control in the absence of p21 may interfere with p14 ARF -induced apoptosis. Finally, these data indicate that the signaling events required for G1 cell cycle arrest and apoptosis induction by p14 ARF dissociate upstream of p53.

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“…22 Similarly, various human tumours exhibit simultaneous loss of p53 and ARF, 24,25 and p14ARF has been reported to limit S-phase progression and colony formation in p53-null human cancer cells. [26][27][28] p19ARF can also inhibit the processing of ribosomal RNA, 29 and the murine and/or human ARF protein interact with other regulators including the E2F transcription factors, 30,31 spinophilin, topoisomerase I, cyclin G, MdmX, 2005; Vol. 4 Issue 3 HIF-1α, pex19p, CARF, p120 E4F , B23, tat-binding protein and Werner's helicase.…”

Section: Introductionmentioning

confidence: 99%

Enforced Expression of p14ARF Induces p53-Dependent Cell Cycle Arrest but Not Apoptosis

Gallagher¹,

Kefford²,

Rizos³

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=1526 KEY WORDS ReportEnforced Expression of p14ARF Induces p53-Dependent Cell Cycle Arrest but Not Apoptosis ABSTRACT Expression of the p14ARF tumour suppressor is induced by hyperproliferative signals produced by RAS, MYC and other oncogenes. p14ARF quenches inappropriate mitogenic signaling by activating the p53 pathway, and the frequent loss of p14ARF in human cancer diminishes the duration and level of the p53 response. Consistent with this role, p14ARF accumulation can induce potent cell cycle arrest, but its role in promoting apoptosis has not been well established. Therefore we investigated the effects of p14ARF on the survival and growth of several human cell types. To avoid the toxicity associated with adenoviral-based vectors, we established inducible expression of p14ARF in p53-intact and p53-deficient human cell lines. As expected, transient and inducible expression of p14ARF induced rapid cell cycle arrest only in tumour cells expressing intact p53. Further, p14ARF expression did not promote apoptosis in primary human fibroblasts, or in any human tumour cell line tested, irrespective of p53 status. Instead, p14ARF expression sensitized cells to apoptosis in the presence of inhibitors of topoisomerase II (adriamycin) and transcription (DRB). Thus, loss of p14ARF would be an important step in the selection of apoptotic resistant tumour cells.

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p14ARF regulates E2F activity

Cited by 57 publications

References 47 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

Loss of p21 disrupts p14ARF-induced G1 cell cycle arrest but augments p14ARF-induced apoptosis in human carcinoma cells

Enforced Expression of p14ARF Induces p53-Dependent Cell Cycle Arrest but Not Apoptosis

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