c-Myc Phosphorylation Is Required for Cellular Response to Oxidative Stress

Benassi, Barbara; Fanciulli, Maurizio; Fiorentino, Francesco; Porrello, Alessandro; Chiorino, Giovanna; Loda, Massimo; Zupi, Gabriella; Biroccio, Annamaria

doi:10.1016/j.molcel.2006.01.009

Cited by 186 publications

(189 citation statements)

References 38 publications

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“…Moreover, we have shown, by using a unique mouse model that, at near-physiological levels of expression in the mammary gland, the Myc T58A mutant, which lacks T58 phosphorylation and has constitutively high S62 phosphorylation, similar to the phosphorylation pattern we report here in breast cancer, is tumorigenic whereas deregulated nearphysiological levels of WT Myc is not (19). Recent reports have demonstrated that pS62 is important for Myc binding to a number of transactivated target genes important for cell proliferation, growth, and survival (34,35). Thus, increased Myc protein stability and altered T58/S62 phosphorylation are likely to play important roles in breast tumorigenesis.…”

Section: Discussionsupporting

confidence: 63%

“…Besides affecting Myc protein stability, Myc phosphorylation also affects its oncogenic activity in that the high-pS62 form of Myc is more oncogenic than the form of Myc lacking pS62 (17,19), suggesting an effect of altering this phosphorylation on Myc target gene regulation. Indeed, recent studies in other laboratories and in our laboratory have demonstrated an important role for pS62 in Myc binding to target gene promoters (34,35) (Fig. S7B).…”

Section: Breast Cancer Cells Have a Switch In Axin1 Splice Variant Exmentioning

confidence: 63%

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Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression

Zhang

Farrell

Daniel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer.T he c-Myc (Myc) oncoprotein is a pleiotropic transcription factor involved in controlling many cellular functions, including cell proliferation, cell growth, and cell differentiation, as well as pathways that regulate genome stability and cell death (1-5). High levels of Myc expression occur in a wide variety of human tumors, and animal models exhibit Myc-induced tumorigenesis in many tissues (6-8). These tumors are often dependent on continued high expression of Myc and withdrawal of Myc can induce tumor regression (8, 9), highlighting the importance of understanding how Myc expression is regulated. In breast cancer, Myc protein is reported to be overexpressed in approximately 50% to 100% of breast tumors depending on the study, whereas only approximately 16% show Myc gene amplification and 22% show increased mRNA expression (6, 10-13). Mechanisms for high Myc expression in human breast tumors lacking gene amplification or elevated mRNA expression have not been reported.Cells have evolved an elegant signaling pathway to help regulate turnover of Myc so that Myc protein levels are kept low when not needed (1,14). In this pathway, sequential and interdependent phosphorylation events on Myc at serine 62 (S62) and threonine 58 (T58) influence Myc stability. Initial phosphorylation of S62 by ERK or CDK kinases in response to mitogen signaling transiently increases Myc stability, whereas subsequent phosphorylation of T58 by GSK3β triggers dephosphorylation of S62 by protein phosphatase 2A-B56α (PP2A-B56α), ubiquitination by the SCF-Fbw7 E3 ligase, and proteasomal degradation (15, 16). Burkitt lymphoma-derived Myc mutations usually occur at or around T58, generally resulting in loss of T58 phosphorylation, elevated S...

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Section: Discussionsupporting

confidence: 63%

Section: Breast Cancer Cells Have a Switch In Axin1 Splice Variant Exmentioning

confidence: 63%

Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression

Zhang

Farrell

Daniel

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Thyroid hormone and cysteine deprivation induce GCLm expression (Dasgupta et al, 2007). Nrf1, Nrf2, AP-1, NFκB and c-Myc seem to be involved in the regulation of the promoter activity of the GCLm gene (Wild et al, 1999;Yang et al, 2005;Benassi et al, 2006). Interestingly, it has been shown that insulin was unable to change the levels of GCLm mRNA (Okouchi et al, 2006), while GCLc levels were affected by this stimulus in the same report.…”

Section: +mentioning

confidence: 73%

S-glutathionylation: relevance in diabetes and potential role as a biomarker

Sánchez‐Gómez

Espinosa‐Díez

Dubey

et al. 2013

Biological Chemistry

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Glutathione is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying deleterious molecules. The oxidative stress induced as a result of a variety of stimuli promotes protein oxidation, usually at cysteine residues, leading to changes in their activity. Mild oxidative stress, which may take place in physiological conditions, induces the reversible oxidation of cysteines to sulfenic acid form, while pathological conditions are associated with higher rates of reactive oxygen species production, inducing the irreversible oxidation of cysteines. Among these, neurodegenerative disorders, cardiovascular diseases and diabetes have been proposed to be pathogenetically linked to this state. In diabetes-associated vascular complications, lower levels of glutathione and increased oxidative stress have been reported. S-glutathionylation has been proposed as a posttranslational modification able to protect proteins from over-oxidizing environments. S-glutathionylation has been identified in proteins involved in diabetic models both in vitro and in vivo. In all of them, S-glutathionylation represents a mechanism that regulates the response to diabetic conditions, and has been described to occur in erythrocytes and neutrophils from diabetic patients. However, additional studies are necessary to discern whether this modification represents a biomarker for the early onset of diabetic vascular complications.

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“…A better understanding of post-transcriptional Myc (c-Myc) regulation in cancer cells is crucial as elevated expression of the Myc protein is observed in B70% of human tumors, whereas only B20% show amplification or translocation in regions of high transcriptional activity (Nesbit et al, 1999;Arnold and Sears, 2008). Physiologic studies in normal GNPs show N-Myc expression is important for cell replication, but N-Myc protein degradation is crucial for cell-cycle exit (Kenney et al, 2004;Sjostrom et al, 2005;Benassi et al, 2006). N-Myc transcription is increased during Shh signaling, with the Cdk1 complex reported to regulate the phosphorylation of serine-62-N-Myc (S62 P -N-Myc, formerly referred to as S54-N-Myc), priming N-Myc for protein degradation (Oliver et al, 2003;Kenney et al, 2004;Sjostrom et al, 2005) before phosphorylation of threonine-58 (T58 P , formerly referred to as T50-N-Myc) by GSK-3b (Sears, 2004;Sjostrom et al, 2005).…”

Section: Introductionmentioning

confidence: 99%