Cytosine methylation transforms an E2F site in the retinoblastoma gene promoter into a binding site for the general repressor methylcytosine- binding protein 2 (MeCP2)

Fiore, Barbara; Palena, Antonella; Felsan, Armando; Palitti, Franco; Caruso, Maurizia; Lavia, Patrizia

doi:10.1093/nar/27.14.2852

Cited by 31 publications

(23 citation statements)

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“…(19,31). Additionally, our observation that pRb is bound to the cdc2, DHFR, and cyclin E promoters at the G 1 /S-phase boundary and during S phase is consistent with data showing increased Rb promoter activity at these same time points (14). Thus, we detected binding of pRb to the promoters of E2F target genes at a time when pRb protein is maximally abundant.…”

Section: Discussionsupporting

confidence: 91%

Target Gene Specificity of E2F and Pocket Protein Family Members in Living Cells

Wells

Boyd

Fry

et al. 2000

Molecular and Cellular Biology

214

218

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E2F-mediated transcription is thought to involve binding of an E2F-pocket protein complex to promoters in the G 0 phase of the cell cycle and release of the pocket protein in late G 1 , followed by release of E2F in S phase. We have tested this model by monitoring protein-DNA interactions in living cells using a formaldehyde cross-linking and immunoprecipitation assay. We find that E2F target genes are bound by distinct E2F-pocket protein complexes which change as cells progress through the cell cycle. We also find that certain E2F target gene promoters are bound by pocket proteins when such promoters are transcriptionally active. Our data indicate that the current model applies only to certain E2F target genes and suggest that Rb family members may regulate transcription in both G 0 and S phases. Finally, we find that a given promoter can be bound by one of several different E2F-pocket protein complexes at a given time in the cell cycle, suggesting that cell cycle-regulated transcription is a stochastic, not a predetermined, process.

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Section: Discussionsupporting

confidence: 91%

Target Gene Specificity of E2F and Pocket Protein Family Members in Living Cells

Wells

Boyd

Fry

et al. 2000

Molecular and Cellular Biology

214

218

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“…One possibility is that CpG methylates the E2F binding sites, as this can affect DNA binding of E2F-1 and, at some promoters, also E2F-2 and E2F-3 (43,44). However, methylation is unlikely to account for the failure of E2F-1 to bind to the MYCN promoter for several reasons.…”

Section: Discussionmentioning

confidence: 99%

“…4). CpG methylation has been shown to prevent binding of E2F proteins to some E2F binding sites (43,44). Therefore, we pre-treated 1A3 cells with the DNA methyltransferase inhibitor 5-aC to remove repressive promoter-methylation prior to the addition of 4-OHT.…”

Section: E2f-1 Induces Ccne1 Expression and Apoptosis In Neuroblastommentioning

confidence: 99%

E2F and Sp1/Sp3 Synergize but Are Not Sufficient to Activate the MYCN Gene in Neuroblastomas

Kramps

Strieder

Sapetschnig

et al. 2004

Journal of Biological Chemistry

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The transcription factors encoded by the MYC genes control diverse tumorigenesis-relevant processes such as cell-cycle progression, growth factor dependence, and response to anti-mitogenic signals (for a review, see Refs. 1 and 2). Overexpression of one of the MYC genes as a result of chromosomal translocation, gene amplification, or loss of negative transcriptional control plays a prominent role in the etiology of many types of tumors (for a review, see Refs. 3 and 4). The MYCN gene is found amplified in several tumors of mostly neuroendocrine origin including about 25% of neuroblastomas, the most common solid tumor in childhood (for a review, see Refs. 5 and 6). Whereas many neuroblastomas regress spontaneously or can be cured with minimal therapy, MYCN-amplified tumors have a poor prognosis. The treatment of these patients has not improved significantly in the course of the last two decades. Recently, the comparison of the gene expression profiles of MYCN-expressing versus non-expressing neuroblastoma cells as well as MYCNamplified versus non-amplified primary tumors have begun to address the functional consequences of the massive overexpression of MYCN resulting from gene amplification (7,8).Several mouse models of Myc-induced tumorigenesis suggest that Myc is not only required for the initiation but also for the maintenance of the tumorigenic state supporting the value of the MYC genes as targets of tumor therapy (9 -11). Roughly half of the drugs that are in clinical use currently act as inhibitors of enzymes. In transcriptional regulation, enzymes are involved mainly as components of signal transduction cascades that relay information to the promoter and as transcriptional co-regulators that modulate local chromatin structure either by covalent modification of histones or by an ATPase-dependent remodeling of nucleosomes (for a review, see Ref. 12). The efficacy of histone deacetylase inhibitors against leukemia has proven the principle of treating cancer by the selective pharmacological modulation of the transcription machinery (13). Application of this concept to the MYCN gene requires a detailed knowledge of the molecular basis of the transcriptional activation of MYCN in neuroblastomas.Toward this goal, we have recently identified the activating members of the E2F family of transcription factors (E2F-1, E2F-2, and E2F-3) as regulators of MYCN expression in neuroblastomas (14). E2F proteins are important regulators of cell-cycle progression, and their activity is negatively controlled by the p16/Rb pathway, which is inactivated in the majority of human cancers (for a review, see Refs. 15 and 16). Although genetic defects of the p16/Rb pathway are rare in neuroblastomas, there is some evidence for a loss of normal control of E2F activity in neuroblastomas by epigenetic means (17).In addition to E2F binding sites, the MYCN promoter contains several putative binding sites for Sp1 and related zinc finger transcription factors (18). One of these, a non-consensus binding site, the CT-box, was previously impli...

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“…A methyl-CpG-dependent complex formed on the sequence MGMGGGAAAAA MG from the promoter of the retinoblastoma gene (Rb) (De Fiore et al 1999), has subsequently been shown by EMSA supershifts to include Kaiso (A. Prokhortchouk, unpubl.).…”

Section: Kaiso Is a Novel Methylated Dna Binding Protein Genes And Devementioning

confidence: 99%

The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor

Prokhortchouk¹,

Hendrich²,

Jørgensen³

et al. 2001

Genes Dev.

453

370

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We describe a novel mammalian DNA binding activity that requires at least two symmetrically methylated CpG dinucleotides in its recognition sequence, preferably within the sequence 5CGCG. A key component of the activity is Kaiso, a protein with POZ and zincfinger domains that is known to associate with p120 catenin. We find that Kaiso behaves as a methylationdependent transcriptional repressor in transient transfection assays. Kaiso is a constituent of one of two methylCpG binding complexes originally designated as MeCP1. The data suggest that zinc-finger motifs are responsible for DNA binding, and may therefore target repression to specific methylated regions of the genome. As Kaiso associates with p120 catenin, Kaiso may link events at the cell surface with DNA methylation-dependent gene silencing.

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Cytosine methylation transforms an E2F site in the retinoblastoma gene promoter into a binding site for the general repressor methylcytosine- binding protein 2 (MeCP2)

Cited by 31 publications

References 0 publications

Target Gene Specificity of E2F and Pocket Protein Family Members in Living Cells

Target Gene Specificity of E2F and Pocket Protein Family Members in Living Cells

E2F and Sp1/Sp3 Synergize but Are Not Sufficient to Activate the MYCN Gene in Neuroblastomas

The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor

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