<i>Max</i>deletion destabilizes MYC protein and abrogates Eµ-<i>Myc</i>lymphomagenesis

Mathsyaraja, Haritha; Freie, Brian; Cheng, Pei-Feng; Babaeva, Ekaterina; Catchpole, Jonathen; Janssens, Derek H.; Henikoff, Steven; Eisenman, Robert N.

doi:10.1101/gad.325878.119

Cited by 45 publications

(45 citation statements)

References 57 publications

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“…This is consistent with studies showing that MGA in association with PRC1.6 occupies E2F and MYC responsive genes in resting (G0) cells (Ogawa et al 2002). A large body of evidence implicates a critical role for MYC and E2F cooperation in maintaining normal tissue homeostasis (Pickering et al 2009, Liu et al 2015, Mathsyaraja et al 2019).…”

Section: Mga As a Myc And E2f Antagonist In Tumorssupporting

confidence: 85%

Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness

Mathsyaraja

Catchpole

Eastwood

et al. 2020

Preprint

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MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of atypical Polycomb PRC1.6, E2F and MYC-MAX targets. Similarly, MGA depletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA, E2F6 and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes PRC1.6 subunits. Lastly, we report that MGA loss has also a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F targets mediated by an atypical Polycomb complex containing MGA-MAX dimers.

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Section: Mga As a Myc And E2f Antagonist In Tumorssupporting

confidence: 85%

Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness

Mathsyaraja

Catchpole

Eastwood

et al. 2020

Preprint

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“…Noteworthy, B-cell-specific deletion of MAX has a modest effect on B-cell development but completely abrogates Eμ-myc -driven lymphomagenesis. Moreover, a study found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets in premalignant Eμ-myc cells, including regulators of MYC stability [ 64 ]. Furthermore, the transcriptional repressor and MAX interactor MNT (MAX Network Transcriptional Repressor), competes with MYC for occupancy at E-box sequences in promoter regions [ 65 ].…”

Section: Transcriptional Regulation Network Involved In Myc-drivenmentioning

confidence: 99%

Insights about MYC and Apoptosis in B-Lymphomagenesis: An Update from Murine Models

Vecchio

Fiume

Correnti

et al. 2020

IJMS

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The balance between cell survival and cell death represents an essential part of human tissue homeostasis, while altered apoptosis contributes to several pathologies and can affect the treatment efficacy. Impaired apoptosis is one of the main cancer hallmarks and some types of lymphomas harbor mutations that directly affect key regulators of cell death (such as BCL-2 family members). The development of novel techniques in the field of immunology and new animal models has greatly accelerated our understanding of oncogenic mechanisms in MYC-associated lymphomas. Mouse models are a powerful tool to reveal multiple genes implicated in the genesis of lymphoma and are extensively used to clarify the molecular mechanism of lymphoma, validating the gene function. Key features of MYC-induced apoptosis will be discussed here along with more recent studies on MYC direct and indirect interactors, including their cooperative action in lymphomagenesis. We review our current knowledge about the role of MYC-induced apoptosis in B-cell malignancies, discussing the transcriptional regulation network of MYC and regulatory feedback action of miRs during MYC-driven lymphomagenesis. More importantly, the finding of new modulators of apoptosis now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.

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“…However, when Myc’s intracellular levels and functions change during tumor development is so far not well understood. In contrast to Myc, Max is a stable and abundant protein, which is not deregulated in cancer, albeit it is essential for Myc-driven lymphomagenesis [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis

Joshi

Eberhardt

Lange

et al. 2020

Cancers

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A major transcriptional output of cells is ribosomal RNA (rRNA), synthesized by RNA polymerase I (Pol I) from multicopy rRNA genes (rDNA). Constitutive silencing of an rDNA fraction by promoter CpG methylation contributes to the stabilization of these otherwise highly active loci. In cancers driven by the oncoprotein Myc, excessive Myc directly stimulates rDNA transcription. However, it is not clear when during carcinogenesis this mechanism emerges, and how Myc-driven rDNA activation affects epigenetic silencing. Here, we have used the Eµ-Myc mouse model to investigate rDNA transcription and epigenetic regulation in Myc-driven B cell lymphomagenesis. We have developed a refined cytometric strategy to isolate B cells from the tumor initiation, promotion, and progression phases, and found a substantial increase of both Myc and rRNA gene expression only in established lymphoma. Surprisingly, promoter CpG methylation and the machinery for rDNA silencing were also strongly up-regulated in the tumor progression state. The data indicate a dichotomous role of oncogenic Myc in rDNA regulation, boosting transcription as well as reinforcing repression of silent repeats, which may provide a novel angle on perturbing Myc function in cancer cells.

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Maxdeletion destabilizes MYC protein and abrogates Eµ-Myclymphomagenesis

Cited by 45 publications

References 57 publications

Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness

Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness

Insights about MYC and Apoptosis in B-Lymphomagenesis: An Update from Murine Models

Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis

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