Reflecting on 25 years with MYC

Meyer, Natalie; Penn, Linda Z.

doi:10.1038/nrc2231

Cited by 1,357 publications

(1,426 citation statements)

References 275 publications

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“…In the future, identification of MYC-positive primary cutaneous angiosarcomas may prove to be of clinical significance, especially in the context of new therapeutic approaches targeting the MYC pathway. 1,13 Disclosure/conflict of interest…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…1 The mechanisms underlying MYC activation include gene amplification, activating mutations, and gene rearrangement, and appear to be different in different tumor types. 1 Relatively recently, MYC amplification has been shown to be a common feature in post-irradiation and chronic lymphedema-associated angiosarcomas (secondary angiosarcomas), where it is presumed to have a key oncogenic role. 2,3 In contrast, initial studies did not find MYC amplification in primary cutaneous or deep soft tissue angiosarcomas, suggesting pathogenetic differences between primary and secondary angiosarcomas.…”

mentioning

confidence: 99%

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MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

et al. 2014

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MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of wellcharacterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sunexposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2-3 þ : 6 cases, 16%; 1 þ : 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2-3 þ immunostaining showed high-level gene amplification. One additional case with 3 þ immunostaining showed higher level aneusomy of chromosome 8 (5-8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3-5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

et al. 2014

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“…Our study pinpointed MYCBP as a direct target of miR-22, thus To test this assertion, we selected several well identified E-box-dependent target genes, which include cyclin D2, cyclin-dependent kinase 4, ornithine decarboxylase, lactate dehydrogenase-A, carbamoyl phosphate synthase-aspartate transcarbamylasedihydroorotase, nucleolin and eukaryotic translation initiation factor 2A. (Patel et al, 2004;Meyer and Penn, 2008). These genes all lack predicted target sites of miR-22 in their 3 0 -UTR as analyzed by TargetScan, thus ruling out a direct interaction between miR-22 and these genes.…”

Section: Mir-22 Might Constitute a Feedback Loop With C-myc And Mycbpmentioning

confidence: 99%

“…Through regulating approximately 15% of all genes, the Myc family of transcription factors (c-Myc, N-Myc and L-Myc) have global effects on cell proliferation and growth as key oncogenic transcription factors (Cole and McMahon, 1999;Nesbit et al, 1999;Meyer and Penn, 2008). The control of c-Myc expression and function involves several mechanisms, one of which is based on the regulatory network of the c-Myc-binding proteins.…”

Section: Introductionmentioning

confidence: 99%

Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

2010

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Oncogenic c-Myc has been described to modulate the expression of a subset of microRNAs (miRNAs), which include miR-22; however, the mechanism through which a miRNA controls c-Myc activity remains unclear. Here we report a novel anti-c-Myc function mediated by miR-22. Ectopically expressed miR-22 inhibited cell proliferation and anchorage-independent growth of human cancer cell lines. Microarray screening and western analyses revealed that miR-22 repressed the c-Mycbinding protein MYCBP, a positive regulator of c-Myc. Consistent with this, reporter assays showed that miR-22-mediated MYCBP gene suppression largely depends on the conserved miR-22 target site within the MYCBP 3 0 -untranslational region (3 0 UTR), implying that MYCBP mRNA is a direct miR-22 target. Depletion of MYCBP using small interfering RNA (siRNA) recapitulated the miR-22-induced anti-growth effect on tumor cells, whereas ectopically expressed MYCBP rescued cells from the growth suppression mediated by miR-22. Moreover, repression of MYCBP by miR-22 downregulated a panel of E-box-containing c-Myc target genes. Our results suggest that miR-22 acts as a tumor suppressor through direct repression of MYCBP expression and subsequent reduction of oncogenic c-Myc activities. As c-Myc inhibits the expression of miR-22, we propose a novel positive feedback loop formed by oncogenic c-Myc to accelerate cell proliferation by suppressing miR-22, a potent inhibitor of MYCBP.

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Inhibition of Myc transcriptional activity by a mini‐protein based upon Mxd1

et al. 2020

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Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini‐protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10‐fold more potent than Omomyc in inhibiting Myc‐driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E‐Box DNA in the promoters of Myc target genes and represses Myc‐mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.

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Reflecting on 25 years with MYC

Cited by 1,357 publications

References 275 publications

MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

Inhibition of Myc transcriptional activity by a mini‐protein based upon Mxd1

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