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Max deletion destabilizes MYC protein and abrogates Eµ-Myc lymphomagenesis.


ABSTRACT: Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.

SUBMITTER: Mathsyaraja H 

PROVIDER: S-EPMC6719623 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Mathsyaraja Haritha H   Freie Brian B   Cheng Pei-Feng PF   Babaeva Ekaterina E   Catchpole Jonathen T JT   Janssens Derek D   Henikoff Steven S   Eisenman Robert N RN  

Genes & development 20190808 17-18


Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of <i>Max</i> has a modest effect on B-cell development but completely abrogates Eµ-<i>Myc-</i>driven lymphomagenesis. While <i>Max</i> loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of <i>Myc</i>-activated genes in premalignant Eµ-<i>Myc</i> cells. We show that the balance  ...[more]

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