Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein

Beaulieu, Marie-Ève; Castillo, Francisco; Soucek, Laura

doi:10.3390/cells9041038

Cited by 64 publications

(57 citation statements)

References 146 publications

(253 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…MYC is one of the most widely investigated cancer-causing genes, being implicated in the formation, maintenance and progression of several different cancer types [1][2][3]. The MYC gene family consists of 3 members, C-MYC, L-MYC and N-MYC, all of which belong to the superfamily of basic helix-loop-helix leucine zipper (bHLHLZ) DNA binding proteins [1][2][3]. MYC proteins largely function as transcriptional modulators, regulating genes involved in several different cellular processes including cell growth, cell cycle, differentiation, apoptosis, angiogenesis, metabolism, DNA repair, protein translation, immune response and stem cell formation [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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MYC as a target for cancer treatment

Duffy

O’Grady

Tang

et al. 2021

Cancer Treatment Reviews

194

103

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The MYC gene which consists of 3 paralogs, C-MYC, N-MYC and L-MYC, is one of the most frequently deregulated driver genes in human cancer. Because of its high prevalence of deregulation and its causal role in cancer formation, maintenance and progression, targeting MYC is theoretically an attractive strategy for treating cancer. As a potential anticancer target, MYC was traditionally regarded as undruggable due to the absence of a suitable pocket for high-affinity binding by low molecular weight inhibitors. In recent years however, several compounds that directly or indirectly inhibit MYC have been shown to have anticancer activity in preclinical tumor models. Amongst the most detailed investigated strategies for targeting MYC are inhibition of its binding to its obligate interaction partner MAX, prevention of MYC expression and blocking of genes exhibiting synthetic lethality with overexpression of MYC. One of the most extensively investigated MYC inhibitors is a peptide/mini-protein known as OmoMYC. OmoMYC, which acts by blocking the binding of all 3 forms of MYC to their target promoters, has been shown to exhibit anticancer activity in a diverse range of preclinical models, with minimal side effects. Based on its broad efficacy and limited toxicity, OmoMYC is currently being developed for evaluation in clinical trials. Although no compound directly targeting MYC has yet progressed to clinical testing, APTO-253, which partly acts by decreasing expression of MYC, is currently undergoing a phase I clinical trial in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MYC as a target for cancer treatment

Duffy

O’Grady

Tang

et al. 2021

Cancer Treatment Reviews

194

103

View full text Add to dashboard Cite

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“…MYC family proteins regulate various biological responses, including cell proliferation, apoptosis, differentiation and senescence. For example, c-MYC promotes cell proliferation by indirectly activating cyclin E/CDK2 through direct transcriptional activation or the downstream target iron transferrin receptor 1 (TFRC1) (19)(20)(21). Furthermore, c-MYC inactivation restored RAS/BRAF-induced senescence, which indicates that continuous MYC signaling is necessary for RAS/BRAF-induced tumorigenesis and tumor progression (21).…”

Section: Correlation Between Mthfd1l Expression and The P53 Signalingmentioning

confidence: 99%

NAD-dependent methylenetetrahydrofolate dehydrogenase inhibits oral squamous cell carcinoma cell proliferation and promotes apoptosis

Zhao¹,

Cheng²,

Lu³

et al. 2021

Transl Cancer Res TCR

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Background: NAD-dependent methylenetetrahydrofolate dehydrogenase catalyzes the conversion of 10-formyltetrahydrofolate to formate in embryonic and adult mammalian mitochondria.Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) is a folate cycle enzyme that is involved in the development of various diseases including cancer. However, the specific mechanisms in oral squamous cell carcinoma (OSCC) are unclear. We analyzed the functional routes of MTHFD1L in OSCC cells.Methods: MTHFD1L expression in OSCC was analyzed using data from The Cancer Genome Atlas (TCGA) database. Then, the levels of mRNA were measured in OSCC and para-tumor oral tissues using Affymetrix microarrays. Additionally, the effects of short hairpin RNA (shRNA)-induced MTHFD1L silencing on the biological behavior of OSCC were assessed in vitro and in vivo, and the potential molecular mechanisms underlying MTHFD1L activity were also investigated.Results: A TCGA database analysis of RNA sequencing revealed that MTHFD1L levels were higher in tumor tissue than in adjacent tissues. Immunohistochemical staining and Kaplan-Meier survival analysis also indicated that MTHFD1L upregulation is associated with a poor prognosis in OSCC. The knockdown of MTHFD1L suppressed cell proliferation, colony formation, and tumorigenesis, while it induced apoptosis in OSCC. Mechanistically, a microarray analysis showed that MTHFD1L suppressed c-MYC and activated p53 signaling by regulating the protein expression of TP53, GADD45A, FAS and JUN.Conclusions: MTHFD1L may be involved in OSCC progression via the c-MYC gene and p53 signaling and may serve as a novel target and orientation for tumor therapy.

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“…While attractive as a drug target, the undruggable nature of the c-MYC protein has also been well described and attributed, at least in part, to its structure and function as a transcription factor. 3,4 With no enzymatic function to inhibit and no well-defined surface binding pockets for drug action, c-MYC has remained elusive in terms of the identification of c-MYC inhibitors as anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%