An Overview of MYC and Its Interactome

Conacci‐Sorrell, Maralice; McFerrin, Lisa; Eisenman, Robert N.

doi:10.1101/cshperspect.a014357

Cited by 351 publications

(429 citation statements)

References 237 publications

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“…Myc proteins function within a transcription factor network (Figure 1A)(Conacci-Sorrell et al, 2014). These proteins form heterodimers with the small bHLHZ protein Max, which bind to E-Box sequences in DNA.…”

Section: Introductionmentioning

confidence: 99%

Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

et al. 2015

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SUMMARY Deregulated Myc transcriptionally reprograms cell metabolism to promote neoplasia. Here we show that oncogenic Myc requires the Myc superfamily member MondoA, a nutrient-sensing transcription factor, for tumorigenesis. Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways resulting in apoptosis. Identification, and knockdown, of genes co-regulated by Myc and MondoA has allowed us to define metabolic functions required by deregulated Myc and demonstrate a critical role for lipid biosynthesis in survival of Myc-driven cancer. Furthermore, overexpression of a subset of Myc and MondoA co-regulated genes correlates with poor outcome of patients with diverse cancers. Co-regulation of cancer metabolism by Myc and MondoA provides the potential for therapeutics aimed at inhibiting MondoA and its target genes.

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Section: Introductionmentioning

confidence: 99%

Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

et al. 2015

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“…MYC's primary mode of deregulation in cancer is through altered levels of MYC protein, resulting in deregulated MYC activity. A broad spectrum of cellular roles has been attributed to MYC in cancer, including regulation of cell cycle, cell proliferation, response to growth factors, ribosome biogenesis, protein synthesis, cell adhesion and cytoskeleton, angiogenesis, metabolic pathways, apoptosis, DNA replication, mRNA capping, and chromatin structure (Amati et al 1998(Amati et al , 2001Facchini and Penn 1998;Nilsson and Cleveland 2003;Hurlin and Dezfouli 2004;Secombe et al 2004;Gallant 2005;Bernard and Eilers 2006;Dang et al 2006Dang et al , 2009Kuttler and Mai 2006;Meyer et al 2006;Cole 2007, 2010; Lebofsky and Walter 2007;Nieminen et al 2007;Shchors and Evan 2007;Sutphin et al 2007;Cole and Cowling 2008;Dai and Lu 2008;Eilers and Eisenman 2008;Hoffman and Liebermann 2008;Meyer and Penn 2008;Prochownik 2008;Herold et al 2009;Lin et al 2009;Ruggero 2009;Singh and Dalton 2009;Dang 2010;van Riggelen et al 2010;Hanahan and Weinberg 2011;Peterson and Ayer 2012;Conacci-Sorrell et al 2013). How does oncogenic MYC activity produce these broad effects?…”

Section: Myc Oncogenic Activity Alters Cellular Gene Expression Programsmentioning

confidence: 99%

MYC and Transcription Elongation

Rahl

Young

2014

Cold Spring Harbor Perspectives in Medicine

101

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Most transcription factors specify the subset of genes that will be actively transcribed in the cell by stimulating transcription initiation at these genes, but MYC has a fundamentally different role. MYC binds E-box sites in the promoters of active genes and stimulates recruitment of the elongation factor P-TEFb and thus transcription elongation. Consequently, rather than specifying the set of genes that will be transcribed in any particular cell, MYC's predominant role is to increase the production of transcripts from active genes. This increase in the transcriptional output of the cell's existing gene expression program, called transcriptional amplification, has a profound effect on proliferation and other behaviors of a broad range of cells. Transcriptional amplification may reduce rate-limiting constraints for tumor cell proliferation and explain MYC's broad oncogenic activity among diverse tissues. TRANSCRIPTIONAL REGULATIONT ranscription factors bind specific DNA sequences and regulate the recruitment and activity of the transcription apparatus at genes (Ptashne and Gann 1997; Lee and Young 2013). The process of transcription consists of at least three steps: initiation, elongation, and termination (Fuda et al. 2009;Malik and Roeder 2010;Zhou et al. 2012). During initiation, the transcription apparatus, which consists of RNA polymerase II (Pol II) and various cofactors, is recruited to genes by transcription factors. A short transcript is produced by Pol II and pause factors typically induce pausing 20 -50 bp downstream of the transcriptional start site. Elongation proceeds after the elongation factor P-TEFb, which consists of Cdk9 and cyclin T, is recruited, and phosphorylates the pause factors and Pol II. Transcription termination is stimulated by recognition of polyadenylation site sequences by factors associated with Pol II during elongation.It has long been clear that specific transcription factors are responsible for recruiting Pol II to selected genes during transcription initiation, but evidence emerged in the last decade that argues for an additional level of control at the pause-release and/or elongation stage of transcription for a large number of genes (Fuda et al. 2009;Nechaev and Adelman 2011;Zhou et al. 2012;Conaway and Conaway 2013). For example, in various human cells, Pol II was found to occupy the promoters of the majority ( 70%) of protein-coding genes, but full-length transcripts were detected at only a subset of these genes (Guenther et al. 2007). Similarly, a large fraction of Drosophila genes with roles in devel-

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“…Nevertheless, it seemed at the time that identification of MYC target genes would be fairly straightforward, and that the identity of its key targets would explain MYC-driven phenotypes in away that proapoptotic (e.g., Puma and Noxa) and antiproliferation (e.g., p21) targets account for the major tumor suppressive effects of p53 (Lowe et al 2004). These hopes for clarity never materialized (see Conacci-Sorrell et al 2014). …”

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confidence: 99%

MYC and the Art of MicroRNA Maintenance

Psathas

Thomas-Tikhonenko

2014

Cold Spring Harbor Perspectives in Medicine

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MYC is a noncanonical transcription factor that binds to thousands of genomic loci and affects .15% of the human transcriptome, with surprisingly little overlap between MYC-bound and -regulated genes. This discordance raises the question whether MYC chooses its targets based on their individual biological effects (“a la carte”) or by virtue of belonging to a certain group of genes (on a “prix fixe” basis). This review presents evidence for a prix fixe, posttranscriptional model where by MYC initially deregulates a select number of microRNAs. These microRNAs then target a broad spectrum of genes based solely on the presence in their 3′ UTRs (untranslated regions) of distinct “seed” sequences. Existing evidence suggests that there are significant microRNA components to all key MYC-driven phenotypes, including cell-cycle progression, apoptosis, metabolism, angiogenesis, metastasis, stemness, and hematopoiesis. Furthermore, each of these cell-intrinsic and -extrinsic phenotypes is likely attributable to deregulation of multiple microRNA targets acting in different, yet frequently overlapping, pathways. The habitual targeting of multiple genes within the same pathway might account for the robustness and persistence of MYC-induced phenotypes.

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An Overview of MYC and Its Interactome

Cited by 351 publications

References 237 publications

Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis

MYC and Transcription Elongation

MYC and the Art of MicroRNA Maintenance

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