The Arf tumor suppressor protein inhibits Miz1 to suppress cell adhesion and induce apoptosis

Herkert, Barbara; Dwertmann, Anne; Herold, Steffi; Abed, Mona; Naud, Jean-François; Finkernagel, Florian; Harms, Gregory S.; Orian, Amir; Wanzel, Michael; Eilers, Martin

doi:10.1083/jcb.200908103

Cited by 40 publications

(38 citation statements)

References 47 publications

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“…This phenomenon is generally accompanied by a parallel disruption of the inhibitory interaction between Mdm2 and p53, resulting in the accumulation of transcriptionally active p53 that induces specific responses such as cell-cycle arrest or apoptosis [11], [12]. However, genetic analysis of tumors and the evidence that ARF can induce cell-cycle arrest in cells lacking Mdm2 and p53 support the notion that ARF might act independently of MDM2 and p53 [2], [5], [13], [14], [15]. Furthermore, the discovery of a plethora of ARF interactors and the observation that also viral, genotoxic, hypoxic and oxidative stresses activate an ARF-dependent response, suggest that ARF has a wider role to protect the cell [16].…”

Section: Introductionmentioning

confidence: 99%

Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

et al. 2013

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The INK4a/ARF locus on the short arm of chromosome 9 is one of the most frequently altered loci in human cancer. It is generally accepted that ARF is involved in oncogenic checkpoint pathways by sensitizing incipient cancer cells to undergo growth arrest or apoptosis through both p53-dependent and independent pathways. While intensive studies have been focused on ARF activation at the transcriptional level, only recently mechanisms governing ARF turnover have been identified. Here, we show for the first time that p14ARF is a PKC target. Prediction analysis showed many potential phosphorylation sites in PKC consensus sequences within ARF protein, and, among them, the threonine at position 8 was the most conserved. Substitution of this threonine influences both ARF stability and localization. Furthermore, a phosphomimetic ARF mutation reduces the ability to arrest cell growth although the ability to bind MDM2 and stabilize p53 result unaffected. Thus we propose that phosphorylation of ARF in both immortalized and tumor cell lines could be a mechanism to escape ARF surveillance following proliferative and oncogenic stress.

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Section: Introductionmentioning

confidence: 99%

Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

et al. 2013

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“…Miz1 is unstable and continuously degraded by the Huwe1 ubiquitin ligase [56]; upon inhibition of Huwe1, Miz1 broadly accumulates at Myc-bound promoters, blunts activation and enhances repression by Myc [56, 57]. Interestingly, the Arf protein binds to and inhibits Huwe1 and promotes association of Myc with Miz1 [58, 59], strongly suggesting that Arf and Miz1 are part of a common stress-response to oncogenic Myc levels.…”

Section: Shaping Transcriptional Amplificationmentioning

confidence: 99%

Taming of the beast: shaping Myc-dependent amplification

Wolf

Lin

Eilers

et al. 2015

Trends in Cell Biology

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Myc deregulation is a hallmark oncogenic event where overexpression of the transcription factor gives rise to numerous tumorigenic phenotypes. The complex consequences of Myc deregulation have obfuscated clear mechanistic interpretations of its function. A synthesis of recent experimental observations offers a consensus on Myc’s direct transcriptional function — when overexpressed, Myc broadly engages the cell’s established euchromatic cis-regulatory landscape where the factor generally amplifies transcription. The level of Myc binding at target genes and the transcriptional output are differentially modulated by additional regulators, including Miz1. Targeting Myc oncogenic activity will require an understanding of whether amplification promotes tumorigenesis and the consequences of amplification in tumors adapted to oncogenic Myc.

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“…Both proteins exhibit anti-proliferative properties, although mediated through different mechanisms by either activating p53 or interacting with the retinoblastoma protein [10]. ARF associates with a number of proteins promoting their posttranslational modification such as sumoylation and phosphorylation to activate or deactivate their function [11, 12]. Among those pathways, the one most frequently studied and best known, is the involvement of ARF in protecting the transcription factor p53 from degradation by binding to MDM2 [13, 14].…”

Section: Introductionmentioning

confidence: 99%

The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A

et al. 2017

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Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.

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The Arf tumor suppressor protein inhibits Miz1 to suppress cell adhesion and induce apoptosis

Abstract: Arf assembles a complex containing Miz1, heterochromatin, and histone H3K3 to block expression of genes involved in cell adhesion and signal transduction. The resulting blockade of cell–cell and cell–matrix interactions facilitates elimination of cells carrying oncogenic mutations.

Cited by 40 publications

References 47 publications

Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

Taming of the beast: shaping Myc-dependent amplification

The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A

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