Mnt transcriptional repressor is functionally regulated during cell cycle progression

Popov, Nikita; Wahlström, Therese; Hurlin, Peter J.; Henriksson, Marie Arsenian

doi:10.1038/sj.onc.1208961

Cited by 31 publications

(26 citation statements)

References 50 publications

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“…However, MYC can also interact directly with HDAC3 to repress canonical targets (Kurland and Tansey 2008). This raises an interesting conundrum, because MXD/MAX and MNT/ MAX complexes also recruit HDAC to repress canonical promoters, such as cyclin D2 (Popov et al 2005). What is the purpose of MYC recruiting both HAT and HDAC activities with opposing functions to canonical promoters?…”

Section: Cofactors Controlling Noncanonical Myc Transcriptional Activmentioning

confidence: 99%

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Hann

2014

Cold Spring Harbor Perspectives in Medicine

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The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency. Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target genes that are regulated by MYC as a means of understanding the molecular mechanisms controlling its diverse roles. Despite significant advances and perhaps because the amount of information learned about MYC is overwhelming, there has been little consensus on the molecular functions of MYC that mediate its critical biological roles. In this perspective, the major MYC cofactors that regulate the various transcriptional activities of MYC, including canonical and noncanonical transactivation and transcriptional repression, will be reviewed and a model of how these transcriptional mechanisms control MYC-mediated proliferation, apoptosis, and tumorigenesis will be presented. The basis of the model is that a variety of cofactors form dynamic MYC transcriptional complexes that can switch the molecular and biological functions of MYC to yield a diverse range of outcomes in a cell-type-and context-dependent fashion.

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Section: Cofactors Controlling Noncanonical Myc Transcriptional Activmentioning

confidence: 99%

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Hann

2014

Cold Spring Harbor Perspectives in Medicine

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“…To repress MYCN expression, doxycycline was added at a final concentration of 1 μg mL −1 . Chromatin immunoprecipitation assays and Western blots were performed as described (44,45). Cell culture, miRNA microarray hybridization and data processing, qPCR, Northern blot, luciferase assays, flow cytometry analysis, transfections, immunohistochemistry, gene expression data analysis, lentiviral transductions, as well as antibodies, constructs, and primers are described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

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

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124

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MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17∼92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-α (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.oncogene | embryonic development | pediatric tumor | transcription factor | hormone receptor N euroblastoma (NB) represents a remarkably heterogeneous pediatric cancer derived from precursor cells of the sympathetic ganglionic lineage, with clinical behavior ranging from spontaneous regression to rapid progression and death (1, 2). Despite the frequent display of multiple genetic defects, including chromosomal gains and losses, aneuploidy, and amplification of chromosomal material, few established molecular genetic markers associate with disease outcome. Amplification of the MYCN locus, present in ≈20 to 30% of all cases, represents the most important genetic aberration, and is strongly related to poor clinical diagnosis (3). MYCN is expressed in the migrating neural crest and encodes a phosphoprotein that belongs to the Myc network of helix-loop-helix leucine zipper transcriptional regulators, which play key roles in governing cell growth, apoptosis, and differentiation (4). Transcriptional activation is mediated by binding of the Myc/Max dimer to the consensus E-box sequence CA(C/T)GTG in target gene promoters while the mechanism of Myc-mediated transcriptional r...

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“…There is some evidence that this interaction is regulated. For example, in the case of MNT, phosphorylation through the ERK pathway has been reported to block its association with mSIN3 (Popov et al 2005). mSIN3 acts as a scaffold that interacts with numerous factors, including class I histone deacetylases (HDAC1 and HDAC2), whose ability to deacetylate histones H3 and H4 in active chromatin is frequently associated with transcriptional silencing (Hassig et al 1997;Laherty et al 1997;Zhang et al 1997).…”

Section: Mxd Proteins Interact With the Msin3 Corepressormentioning

confidence: 99%

An Overview of MYC and Its Interactome

Conacci‐Sorrell

McFerrin

Eisenman

2014

Cold Spring Harbor Perspectives in Medicine

357

398

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This review is intended to provide a broad outline of the biological and molecular functions of MYC as well as of the larger protein network within which MYC operates. We present a view of MYC as a sensor that integrates multiple cellular signals to mediate a broad transcriptional response controlling many aspects of cell behavior. We also describe the larger transcriptional network linked to MYC with emphasis on the MXD family of MYC antagonists. Last, we discuss evidence that the network has evolved for millions of years, dating back to the emergence of animals.

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Mnt transcriptional repressor is functionally regulated during cell cycle progression

Cited by 31 publications

References 50 publications

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

An Overview of MYC and Its Interactome

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