An unsteady scaffold for Myc

Schülein, Christina; Eilers, Martin

doi:10.1038/emboj.2009.14

Cited by 8 publications

(6 citation statements)

References 12 publications

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“…MYC amplification is found in a high proportion of tumors with Brca1 alterations, as well as in ERα-negative, basal-like tumors [ 34 , 35 ]. Despite intense screening efforts, point mutations of Myc have not been described in breast or other carcinomas [ 36 ]. Other mechanisms promoting increased Myc levels, however, have been found.…”

Section: Background On Myc In Breast Cancermentioning

confidence: 99%

Key signalling nodes in mammary gland development and cancer: Myc

Hynes

Stoelzle

2009

Breast Cancer Res

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Myc has been intensely studied since its discovery more than 25 years ago. Insight has been gained into Myc's function in normal physiology, where its role appears to be organ specific, and in cancer where many mechanisms contribute to aberrant Myc expression. Numerous signals and pathways converge on Myc, which in turn acts on a continuously growing number of identified targets, via transcriptional and nontranscriptional mechanisms. This review will concentrate on Myc as a signaling mediator in the mammary gland, discussing its regulation and function during normal development, as well as its activation and roles in breast cancer.

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Section: Background On Myc In Breast Cancermentioning

confidence: 99%

Key signalling nodes in mammary gland development and cancer: Myc

Hynes

Stoelzle

2009

Breast Cancer Res

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“…and protein phosphatase 2A (PP2A), which in turn leads to Mycʼs ubiquitination by the E3 ubiquitin ligase Fbw7 and subsequent degradation. These different reactions are facilitated by the scaffolding protein Axin, which binds several of the involved proteins, including Myc (reviewed by Sears, 2004;Schulein and Eilers, 2009).…”

Section: Control Of Myc Protein Levelsmentioning

confidence: 99%

Chapter 5 Drosophila Myc

Gallant

2009

Advances in Cancer Research

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Myc genes play a major role in human cancer, and they are important regulators of growth and proliferation during normal development. Despite intense study over the last three decades, many aspects of Myc function remain poorly understood. The identification of a single Myc homolog in the model organism Drosophila melanogaster more than 10 years ago has opened new possibilities for addressing these issues. This review summarizes what the last decade has taught us about Myc biology in the fruit fly.

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“…When RAS is activated through external stimuli or mutation, two distinct cellular pathways are activated: the RAF/MEK/ERK and PI3/PDK1/AKT/GSK3 pathways. These pathways in turn affect the stability of MYC family proteins ( 7 – 9 ) ( Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Aurora kinase A is a possible target of OSU-03012 to destabilize MYC family proteins

et al. 2014

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OSU-03012, a 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitor, destabilizes MYCN and MYC proteins in neuroblastoma cells. However, AKT phosphorylation is barely detectable in neuroblastoma cells under normal culture conditions whether treated with OSU-03012 or not. This observation suggests that PDK1 is not the main target of OSU-03012 to destabilize MYC and MYCN in neuroblastoma cells. In the present study, we explored one of the possible mechanisms by which OSU-03012 destabilizes MYC and MYCN. Since Aurora kinase A is reported to phosphorylate GSK3β, leading to its inactivation, we hypothesized that one of the targets of OSU-03012 is Aurora kinase A. Comparative analysis of OSU-03012 and VX-680, a potent and specific inhibitor of Aurora kinases, showed that both inhibitors destabilized MYC and MYCN and were significantly growth suppressive to neuroblastoma cell lines. In silico molecular docking analysis further showed that the calculated interaction energy between Aurora kinase A and OSU-03012 was −109.901 kcal/mol, which was lower than that (−89.273 kcal/mol) between Aurora kinase A and FXG, an Aurora kinase-specific inhibitor. Finally, an in vitro Aurora kinase A inhibition assay using a recombinant Aurora kinase A showed that OSU-03012 significantly inhibited Aurora kinase A, although it was weaker in potency than that of VX-680. Thus, OSU-03012 has a likelihood of binding to and inhibiting Aurora kinase A in vivo. These results suggest that OSU-03012 affects multiple cellular targets, including Aurora kinase A, to exhibit its growth suppressive and MYC and MYCN-destabilizing effects on neuroblastoma and other cancer cells.

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An unsteady scaffold for Myc

Abstract: Correction to: The EMBO Journal (2009) 28, 453–454. doi:10.1038/emboj.2009.1

Cited by 8 publications

References 12 publications

Key signalling nodes in mammary gland development and cancer: Myc

Key signalling nodes in mammary gland development and cancer: Myc

Chapter 5 Drosophila Myc

Aurora kinase A is a possible target of OSU-03012 to destabilize MYC family proteins

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