Stopping MYC in its tracks

Stefan, Eduard; Hart, Jonathan R.; Bister, Klaus

doi:10.18632/aging.100780

Cited by 2 publications

(2 citation statements)

References 7 publications

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“…Carcinogenesis can be regarded as a consequence of pathological alterations in molecular interactions and signaling pathways. Deregulated Myc expression affects the level of Myc:Max complexes and disturbes the physiological equilibrium in the entire Myc–Max network, leading ultimately to the initiation and progression of cancer [ 2 , 5 , 6 , 10 , 29 ]. Therefore, investigations of dynamic molecular interactions are crucial in order to reveal the underlying regulatory mechanisms of complex formations in this network.…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent binding of Myc to calmodulin

et al. 2016

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The bHLH-LZ (basic region/helix-loop-helix/leucine zipper) oncoprotein Myc and the bHLH-LZ protein Max form a binary transcription factor complex controlling fundamental cellular processes. Deregulated Myc expression leads to neoplastic transformation and is a hallmark of most human cancers. The dynamics of Myc transcription factor activity are post-translationally coordinated by defined protein-protein interactions. Here, we present evidence for a second messenger controlled physical interaction between the Ca2+ sensor calmodulin (CaM) and all Myc variants (v-Myc, c-Myc, N-Myc, and L-Myc). The predominantly cytoplasmic Myc:CaM interaction is Ca2+-dependent, and the binding site maps to the conserved bHLH domain of Myc. Ca2+-loaded CaM binds the monomeric and intrinsically disordered Myc protein with high affinity, whereas Myc:Max heterodimers show less, and Max homodimers no affinity for CaM. NMR spectroscopic analyses using alternating mixtures of 15N-labeled and unlabeled preparations of CaM and a monomeric Myc fragment containing the bHLH-LZ domain corroborate the biochemical results on the Myc:CaM interaction and confirm the interaction site mapping. In electrophoretic mobility shift assays, addition of CaM does not affect high-affinity DNA-binding of Myc:Max heterodimers. However, cell-based reporter analyses and cell transformation assays suggest that increasing CaM levels enhance Myc transcriptional and oncogenic activities. Our results point to a possible involvement of Ca2+ sensing CaM in the fine-tuning of Myc function.

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Section: Discussionmentioning

confidence: 99%

Calcium-dependent binding of Myc to calmodulin

et al. 2016

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“…In view of the strikingly broad involvement of MYC family genes in virtually all human cancers, strategies to interfere with MYC -induced oncogenesis, directly or indirectly, are an obviously urgent goal in cancer research and clinical treatment (Soucek et al 2008; Prochownik and Vogt 2010; Dang 2012; McKeown and Bradner 2014; Stefan et al 2015). A genetic approach using an engineered dominant negative MYC mutant with altered dimerization specificity provided principal proof of guided MYC inhibition as a means to interfere with cell transformation.…”

Section: Pharmacological Interferencementioning

confidence: 99%

MYC and RAF: Key Effectors in Cellular Signaling and Major Drivers in Human Cancer

Stefan

Bister

2017

Current Topics in Microbiology and Immunology

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The prototypes of the human MYC and RAF gene families are orthologs of animal proto-oncogenes that were originally identified as transduced alleles in the genomes of highly oncogenic retroviruses. MYC and RAF genes are now established as key regulatory elements in normal cellular physiology, but also as major cancer driver genes. Although the predominantly nuclear MYC proteins and the cytoplasmic RAF proteins have different biochemical functions, they are functionally linked in pivotal signaling cascades and circuits. The MYC protein is a transcription factor and together with its dimerization partner MAX holds a central position in a regulatory network of bHLH-LZ proteins. MYC regulates transcription conducted by all RNA polymerases and controls virtually the entire transcriptome. Fundamental cellular processes including distinct catabolic and anabolic branches of metabolism, cell cycle regulation, cell growth and proliferation, differentiation, stem cell regulation, and apoptosis are under MYC control. Deregulation of MYC expression by rearrangement or amplification of the MYC locus or by defects in kinase-mediated upstream signaling, accompanied by loss of apoptotic checkpoints, leads to tumorigenesis and is a hallmark of most human cancers. The critically controlled serine/threonine RAF kinases are central nodes of the cytoplasmic MAPK signaling cascade transducing converted extracellular signals to the nucleus for reshaping transcription factor controlled gene expression profiles. Specific mutations of RAF kinases, such as the prevalent BRAF(V600E) mutation in melanoma, or defects in upstream signaling or feedback loops cause decoupled kinase activities which lead to tumorigenesis. Different strategies for pharmacological interference with MYC- or RAF-induced tumorigenesis are being developed and several RAF kinase inhibitors are already in clinical use.

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Stopping MYC in its tracks

Cited by 2 publications

References 7 publications

Calcium-dependent binding of Myc to calmodulin

Calcium-dependent binding of Myc to calmodulin

MYC and RAF: Key Effectors in Cellular Signaling and Major Drivers in Human Cancer

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