Regulation of c-Myc through Phosphorylation at Ser-62 and Ser-71 by c-Jun N-Terminal Kinase

Noguchi, Kohji; Kitanaka, Chifumi; Yamana, Hironobu; Kokubu, Akiko; Mochizuki, Takuro; Kuchino, Yoshiyuki

doi:10.1074/jbc.274.46.32580

Cited by 173 publications

(135 citation statements)

References 48 publications

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“…We showed earlier that ectopic expression of c-myc oncogene could rescue the impaired Ras transformation of the Jnk2À/À MEFs (Nielsen et al, 2007). Because both ERK and JNK can phosphorylate Ser 62 in c-Myc and thus increase c-Myc stability (Noguchi et al, 1999), we investigated c-Myc phosphorylation and found it to be lower in Jnk2À/À cells than in wt cells (Figure 2a). Consequently, also the c-Myc levels were down in the Jnk2À/À þ Ras MEFs ( Figure 2a).…”

Section: Resultsmentioning

confidence: 84%

Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

et al. 2011

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Ras is one of the most frequently activated oncogenes in cancer. Two mitogen-activated protein kinases (MAPKs) are important for ras transformation: extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 2 (JNK2). Here we present a downstream signal amplification cascade that is critical for ras transformation in murine embryonic fibroblasts. This cascade is coordinated by ERK and JNK2 MAPKs, whose Rasmediated activation leads to the enhanced levels of three oncogenic transcription factors, namely, c-Myc, activating transcription factor 2 (ATF2) and ATF3, all of which are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation.

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Section: Resultsmentioning

confidence: 84%

Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

et al. 2011

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“…Furthermore over-expression of c-myc in beta cells of transgenic mice resulted in increased apoptosis and decreased insulin gene expression [40]. The ability of c-myc to mediate cytokine-induced apoptosis appears to be dependent on phosphorylation of this proto-oncogene by mitogen activated protein kinase (MAPK) or c-Jun NH2-terminal kinase (JNK) [41,42]. Interestingly, JNK is activated by IL-1β in beta cells and JNK inhibition has been shown to prevent IL-1β-mediated beta cell apoptosis [43].…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles during beta cell maturation and after IL-1? exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1? sensitivity

et al. 2004

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Aim/hypothesis. Maturation of the beta cells in the islets of Langerhans is dependent upon sequential activation of different transcription factors such as Pdx-1 and Nkx6.1. This maturation is associated with an acquired sensitivity to cytokines and may eventually lead to type 1 diabetes. The aims of this study were to characterise changes in mRNA expression during beta cell maturation as well as after interleukin-1β (IL-1β) exposure. Methods. Transcriptome analyses were performed on two phenotypes characterised as a glucagon-producing pre-beta-cell phenotype (NHI-glu), which matures to an IL-1β-sensitive insulin-producing beta cell phenotype (NHI-ins). Beta cell lines over-expressing Pdx-1 or Nkx6.1, respectively, were used for functional characterisation of acquired IL-1β sensitivity.Results. During beta cell maturation 98 fully annotated mRNAs changed expression levels. Of these, 50 were also changed after 24 h of IL-1β exposure. In addition, 522 and 197 fully annotated mRNAs, not affected by maturation, also changed expression levels following IL-1β exposure of the beta cell and the prebeta-cell phenotype, respectively. Beta cell maturation was associated with an increased expression of Nkx6.1, whereas both Pdx-1 and Nkx6.1 expression were decreased following IL-1β exposure. Over-expression of Nkx6.1 or Pdx-1 in cell lines resulted in a significantly increased sensitivity to IL-1β. Conclusions/interpretation. These results suggest that the final beta cell maturation accompanied by increased IL-1β sensitivity is, in part, dependent upon the expression of genes regulated by Pdx-1 and Nkx6.1. Future classification of the genes regulated by these transcription factors and changed during beta cell maturation should elucidate their role in the acquired sensitivity to IL-1β and may be helpful in identifying new targets for intervention/prevention strategies.

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“…Furthermore, there is substantial evidence that phosphorylation of these sites plays a role in regulating c-Myc's various biological activities (Henriksson et al, 1993;Pulverer et al, 1994;Noguchi et al, 1999;Change et al, 2000). Through phosphopeptide mapping analysis, we've now shown that B-Myc is phosphorylated at Ser-60 and Ser-68, homologous to Ser-62 and Ser-71 of c-Myc, with Ser-68 being the major phosphorylation site.…”

Section: B-myc Is a Short-lived Nuclear Phosphoproteinmentioning

confidence: 99%

“…This is somewhat surprising as Thr-58 is a major phosphorylation site in c-Myc, especially when c-Myc is overexpressed (Lutterbach and , and this region is conserved between c-Myc and B-Myc. It was recently shown that c-Myc is a substrate for phosphorylation by the stress-activated kinase JNK at Ser-62 and Ser-71 (Noguchi et al, 1999). Thus, BMyc may also be subject to phosphorylation by JNK, at Ser-60 and Ser-68, which could serve to regulate BMyc activity in response to extracellular stress.…”

Section: B-myc Is a Short-lived Nuclear Phosphoproteinmentioning

confidence: 99%

B-Myc is preferentially expressed in hormonally-controlled tissues and inhibits cellular proliferation

2000

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The myc family of genes plays an important role in several cellular processes including proliferation, apoptosis, di erentiation, and transformation. B-myc, a relatively new and largely unstudied member of the myc family, encodes a protein that is highly homologous to the N-terminal transcriptional regulatory domain of cMyc. Here, we show that high level B-myc expression is restricted to speci®c mouse tissues, primarily hormonally-controlled tissues, with the highest level of expression in the epididymis. We also report the identi®cation of the endogenous B-Myc protein from mouse tissues. Like other Myc family proteins, B-Myc is a short-lived nuclear protein which is phosphorylated on residues Ser-60 and Ser-68. Rapid proteolysis of B-Myc occurs via the ubiquitin-proteasome pathway. Finally, we found that overexpression of B-Myc signi®cantly slows the growth of Rat 1a ®broblasts and COS cells suggesting B-Myc functions as an inhibitor of cellular proliferation.

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Regulation of c-Myc through Phosphorylation at Ser-62 and Ser-71 by c-Jun N-Terminal Kinase

Cited by 173 publications

References 48 publications

Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

Gene expression profiles during beta cell maturation and after IL-1? exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1? sensitivity

B-Myc is preferentially expressed in hormonally-controlled tissues and inhibits cellular proliferation

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