Fine-tuned amplification in cells

Dang, Chi V.

doi:10.1038/nature13518

Cited by 26 publications

(24 citation statements)

References 12 publications

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“…While some have suggested that there seems no pattern for MYC-regulated genes1012, recent evidence indicates that the models for MYC regulation could be context dependent: MYC exerts different roles under normal development and oncogenic conditions1362. Interestingly, the same context-dependent regulation is likely to be true with the activity of Menin, which serves both as a tumour suppressor and oncoprotein, pending on different circumstances.…”

Section: Discussionmentioning

confidence: 99%

Menin enhances c-Myc-mediated transcription to promote cancer progression

Yuan

Shen

et al. 2017

Nat Commun

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Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism both in vitro and in vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.

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Section: Discussionmentioning

confidence: 99%

Menin enhances c-Myc-mediated transcription to promote cancer progression

Yuan

Shen

et al. 2017

Nat Commun

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“…Interestingly, it has been suggested recently that cMyc is posed to amplify all the extant expressed genes [35,36]. More recently, new evidence emerges to reveal that cMyc selectively fine-tunes expression of many important genes essential for cell growth and cancer progression [37][38][39]. All these results point to the enigmatic roles and underlying mechanisms for cMyc yet to be further elucidated under developmental or oncogenic circumstances.…”

Section: Introductionmentioning

confidence: 91%

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

et al. 2015

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Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

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“…This mechanism may help to explain the differential expression of genes in tumors associated with high levels of MYC activated by oncogenic mechanisms (Figure 1). 15 MYC activation has a profound influence in many different cell functions including cell proliferation and growth, DNA replication, metabolism and energy regulation, and protein and nucleotide biosynthesis, among others. Cell proliferation is modulated by the control of checkpoint genes such as GADD45 and the direct or indirect regulation of several cyclins, CDKs, and their respective inhibitors.…”

Section: Myc Functions and Regulationmentioning

confidence: 99%