Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Li, Wei; You, Li Ru; Cooper, Jonathan M.; Schiavon, Gaia; Pepe-Caprio, Angela; Zhou, Lü; Ishii, Ryohei; Giovannini, Marco; Hanemann, C. Oliver; Long, Stephen B.; Erdjument‐Bromage, Hediye; Zhou, Pengbo; Tempst, Paul; Giancotti, Filippo G.

doi:10.1016/j.cell.2010.01.029

Cited by 294 publications

(406 citation statements)

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“…Through binding to Vpr, VprBP allows Vpr to modulate the intrinsic catalytic activity of the CUL4-DDB1 complex, which in turn leads to the induction of G 2 phase cell cycle arrest in the virus-infected cells. The direct interaction of tumor suppressor Merlin with VprBP is shown to be an integral part of the mechanism by which Merlin inhibits CUL4-DDB1 ubiquitin E3 ligase to suppress tumorigenesis (22). Furthermore, the observation that VprBP-depleted cells activate DNA damage checkpoints and increase the cellular level of CDK inhibitor p21 suggests that VprBP is involved in the control of cell cycle arrest and apoptosis (11).…”

mentioning

confidence: 99%

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Kim

Heo

Choi

et al. 2012

Molecular and Cellular Biology

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HIV-1 Vpr-binding protein (VprBP) has been implicated in the regulation of both DNA replication and cell cycle progression, but its precise role remains unclear. Here we report that VprBP regulates the p53-induced transcription and apoptotic pathway. VprBP is recruited to p53-responsive promoters and suppresses p53 transactivation in the absence of stress stimuli. To maintain target promoters in an inactive state, VprBP stably binds to nucleosomes by recognizing unacetylated H3 tails. Promoterlocalized deacetylation of H3 tails is a prerequisite for VprBP to tether and act as a bona fide inhibitor at p53 target genes. VprBP knockdown leads to activation of p53 target genes and causes an increase in DNA damage-induced apoptosis. Moreover, phosphorylation of VprBP at serine 895 impairs the ability of VprBP to bind H3 tails and to repress p53 transactivation. Our results thus reveal a new role for VprBP in regulation of the p53 signaling pathway, as well as molecular mechanisms of cancer development related to VprBP misregulation. VprBP was first identified as a protein that can interact with HIV-1 viral protein R by coimmunoprecipitation assays (37). VprBP is a 1,507-amino-acid protein that contains conserved domains, including YXXY repeats, the Lis homology motif, and WD40 repeats. Despite the lack of molecular characterization of VprBP, recent studies suggest that VprBP can specifically associate with DDB1 to act as a substrate recognition subunit of the CUL4-DDB1 ubiquitin E3 ligase complex (12,20,26,33,36,38). Through binding to Vpr, VprBP allows Vpr to modulate the intrinsic catalytic activity of the CUL4-DDB1 complex, which in turn leads to the induction of G 2 phase cell cycle arrest in the virus-infected cells. The direct interaction of tumor suppressor Merlin with VprBP is shown to be an integral part of the mechanism by which Merlin inhibits CUL4-DDB1 ubiquitin E3 ligase to suppress tumorigenesis (22). Furthermore, the observation that VprBP-depleted cells activate DNA damage checkpoints and increase the cellular level of CDK inhibitor p21 suggests that VprBP is involved in the control of cell cycle arrest and apoptosis (11).p53 is an important tumor suppressor which induces either cell cycle arrest or apoptosis in response to DNA damage (27,30,34). p53 regulates these processes mainly by acting as a sequencespecific DNA binding factor that regulates transcription of a number of target genes. p53 regulates the transcription reaction, to a large extent, at the level of chromatin, which establishes a physical barrier for the binding of transcription factors to the promoter region of a target gene. The most dynamic parts of chromatin are amino-terminal domains (called histone "tails") of core histones, which protrude from the DNA. The major contributions of individual histone tails in gene transcription are made through their posttranslational modifications (3,18,21,29,35). Among various modifications, histone acetylation has been implicated as a critical mark for activation of p53 target genes (1,5,7,10,13...

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mentioning

confidence: 99%

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Kim

Heo

Choi

et al. 2012

Molecular and Cellular Biology

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“…The subcellular distribution of the Merlin protein is critical for its tumor-suppression activity. Merlin has been shown to inhibit mitogenic signaling by binding to the E3 ubiquitin ligase CRL4 DCAF1 in the nucleus (34). How the protein translocates between different cellular compartments and reaches the nucleus remains unknown, however.…”

Section: Discussionmentioning

confidence: 99%

Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants

Benseñor

Barlan²,

Rice

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The neurofibromatosis type 2 (NF2) tumor-suppressor protein Merlin is a member of the ERM family of proteins that links the cytoskeleton to the plasma membrane. In humans, mutations in the NF2 gene cause neurofibromatosis type-2 (NF2), a cancer syndrome characterized by the development of tumors of the nervous system. Previous reports have suggested that the subcellular distribution of Merlin is critical to its function, and that several NF2 mutants that lack tumor-suppressor activity present improper localization. Here we used a Drosophila cell culture model to study the distribution and mechanism of intracellular transport of Merlin and its mutants. We found that Drosophila Merlin formed cytoplasmic particles that move bidirectionally along microtubules. A single NF2-causing amino acid substitution in the FERM domain dramatically inhibited Merlin particle movement. Surprisingly, the presence of this immotile Merlin mutant also inhibited trafficking of the WT protein. Analysis of the movement of WT protein using RNAi and pull-downs showed that Merlin particles are associated with and moved by microtubule motors (kinesin-1 and cytoplasmic dynein), and that binding of motors and movement is regulated by Merlin phosphorylation. Inhibition of Merlin transport by expression of the dominant-negative mutant or depletion of kinesin-1 results in increased nuclear accumulation of the transcriptional coactivator Yorkie. These results demonstrate the requirement of microtubule-dependent transport for Merlin function.M erlin is a tumor-suppressor protein of the ERM family encoded by the NF2 gene that controls cell growth and contact-dependent inhibition of proliferation. Mutations in the NF2 gene are the underlying cause of neurofibromatosis type 2 (NF2), a familial cancer syndrome characterized by the development of sporadic tumors of the nervous system (1-3). To gain insight into Merlin's cellular functions, we have studied a Drosophila Merlin homolog and its disease-causing mutant. Drosophila Merlin shares the same fundamental domain composition as its mammalian counterpart, and several groups have obtained comparable results using the mammalian and Drosophila proteins (4).Merlin functions by organizing membrane domains that connect signals coming from the extracellular environment to cytoplasmic factors to ultimately regulate cellular proliferation (5-7). Consistent with this role, Merlin is concentrated in actin-rich structures, such as membrane ruffles in isolated cells and at cell-cell contacts in dense cultures (8-10). Merlin also exhibits a punctate distribution that has been attributed to localization to intracellular vesicles (7,11,12). Merlin has a dynamic distribution in Drosophila S2 cells. Studies have shown that the protein is initially localized along the cell cortical region and is then internalized in the form of particles (12, 13).Merlin mislocalization is associated with abnormal tissue growth and proliferation (12, 13). Many NF2 mutations of Merlin are abnormally distributed in the cells and lack tumor...

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“…Members of the CRL4 E3 ligase family regulate chromatin remodelling, DNA replication and the response to DNA damage. Although the physiological substrates of CRL4 DCAF1 have not yet been identified, gene expression analysis suggests that CRL4 DCAF1 regulates a broad gene expression programme, consisting of more than 1,000 genes [35]. CRL4 DCAF1 could exert this effect by [111], seems to be inhibited at the tran- [111], seems to be inhibited at the tran-, seems to be inhibited at the transcriptional level by Merlin expression as well as DCAF1 knockdown [35].…”

Section: Nuclear Inhibition Of Crl4 Dcaf1mentioning

confidence: 99%

“…Although the physiological substrates of CRL4 DCAF1 have not yet been identified, gene expression analysis suggests that CRL4 DCAF1 regulates a broad gene expression programme, consisting of more than 1,000 genes [35]. CRL4 DCAF1 could exert this effect by [111], seems to be inhibited at the tran- [111], seems to be inhibited at the tran-, seems to be inhibited at the transcriptional level by Merlin expression as well as DCAF1 knockdown [35]. Irrespective of the specific mechanism by which CRL4 DCAF1 regulates gene expression, the breadth of the oncogenic gene expression programme it induces and the identity of some of the genes regulated suggest that Merlin could suppress several mitogenic signalling pathways by inhibiting CRL4 DCAF1 .…”

Section: Nuclear Inhibition Of Crl4 Dcaf1mentioning

confidence: 99%

“…In addition, it has become clear that Merlin translocates to the nucleus to modify Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus review The tumour suppressor Merlin gene expression through inhibition of the E3 ubiquitin ligase CRL4 DCAF1 [35]. In this review, we discuss these recent results and the models of Merlin function they suggest, in an effort to provide a framework for future studies.…”

Section: Introductionmentioning

confidence: 97%

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Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

et al. 2012

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Inhibition of proliferation by cell-to-cell contact is essential for tissue organization, and its disruption contributes to tumorigenesis. The FERM domain protein Merlin, encoded by the NF2 tumour suppressor gene, is an important mediator of contact inhibition. Merlin was thought to inhibit mitogenic signalling and activate the Hippo pathway by interacting with diverse target-effectors at or near the plasma membrane. However, recent studies highlight that Merlin pleiotropically affects signalling by migrating into the nucleus and inducing a growth-suppressive programme of gene expression through its direct inhibition of the CRL4 DCAF1 E3 ubiquitin ligase. In addition, Merlin promotes the establishment of epithelial adhesion and polarity by recruiting Par3 and aPKC to E-cadherin-dependent junctions, and by ensuring the assembly of tight junctions. These recent advances suggest that Merlin acts at the cell cortex and in the nucleus in a similar, albeit antithetic, manner to the oncogene β-catenin.

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Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Cited by 294 publications

References 51 publications

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Microtubule-mediated transport of the tumor-suppressor protein Merlin and its mutants

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

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