Abstract
It is classically recognized that the physiological and oncogenic functions of Myc proteins depend on specific DNA binding enabled by the dimerization of its C-terminal basic-region-Helix-Loop-Helix-Leucine Zipper (b-HLH-LZ) domain with that of Max. However, a new paradigm is emerging, where the binding of the c-Myc/Max heterodimer to non-specific sequences in enhancers and promoters drives the transcription of genes involved in diverse oncogenic programs. Importantly, Max can form a stable homodimer even in the presence of c-Myc and bind DNA (specific and non-specific) with comparable affinity to the c-Myc/Max heterodimer. Intriguingly, alterations in the Max gene by germline and somatic mutations or changes in the gene product by alternative splicing (e.g. ΔMax) were recently associated with pheochromocytoma and glioblastoma, respectively. This has led to the proposition that Max is, by itself, a tumor suppressor. However, the actual mechanism through which it exerts such an activity remains to be elucidated. Here, we show that contrary to the WT motif, the b-HLH-LZ of ΔMax does not homodimerize in the absence of DNA. In addition, although ΔMax can still bind the E-box sequence as a homodimer, it cannot bind non-specific DNA in that form, while it can heterodimerize with c-Myc and bind E-box and non-specific DNA as a heterodimer with high affinity. Taken together, our results suggest that the WT Max homodimer is important for attenuating the binding of c-Myc to specific and non-specific DNA, whereas ΔMax is unable to do so. Conversely, the splicing of Max into ΔMax could provoke an increase in overall chromatin bound c-Myc. According to the new emerging paradigm, the splicing event and the stark reduction in homodimer stability and DNA binding should promote tumorigenesis impairing the tumor suppressor activity of the WT homodimer of Max.
Highlights
Myc proteins (N, L- and c-Myc) are basic region-Helix-Loop-Helix-Leucine Zipper (b-HLHLZ) transcriptional regulators with a broad spectrum of physiological and oncogenic target genes [1,2,3]
Sustained expression and persistent levels of Myc proteins caused by mutations in other oncogenes such as EGFR and RAS can amplify the transcription of oncogenic genes or programs and lead to the addiction of tumor cells to such programs [6]
It was recently shown that high levels of c-Myc caused by the constitutive activity of EGFRvIII, a mutated form of EGFR, amplifies the transcription of hnRNPA1 in glioblastoma multiforme (GBM) and the alternative splicing of Max into its C-terminally truncated ΔMax isoform [11]
Summary
Myc proteins (N-, L- and c-Myc) are basic region-Helix-Loop-Helix-Leucine Zipper (b-HLHLZ) transcriptional regulators with a broad spectrum of physiological and oncogenic target genes [1,2,3]. Sustained expression and persistent levels of Myc proteins caused by mutations in other oncogenes such as EGFR and RAS can amplify the transcription of oncogenic genes or programs and lead to the addiction of tumor cells to such programs [6]. This mechanism of addiction is strongly supported by studies and data that demonstrate the invasion of transcriptionally active chromatin (enhancers and promoters)—often devoid of E-box sequences—by persistent and high levels of Myc [7,8]. This spill-over to sites where no E-boxes are found can be explained by the fact that b-HLH-LZ transcription factors can bind to E-box and non-E-box DNA sequences with high and almost comparable affinities [9]
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