Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation

Hydbring, Per; Bahram, Fuad; Su, Yingtao; Tronnersjö, Susanna; Högstrand, Kari; Lehr, Natalie von der; Sharifi, H R; Lilischkis, Richard; Hein, Nadine; Wu, Siqin; Vervoorts, Jörg; Henriksson, Marie Arsenian; Grandien, Alf; Lüscher, Bernhard; Larsson, Lars‐Gunnar

doi:10.1073/pnas.0900121106

Cited by 174 publications

(192 citation statements)

References 45 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: 60%

“…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: 64%

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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: 60%

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

confidence: 64%

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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“…CDK2 has also been previously implicated as a possible target to induce senescence, specifically in MYC-transformed cells that have circumvented the senescent response (18). Interestingly, MYC was found to be itself a target of CDK2, and, in cells cotransformed by MYC and RAS, MYC was able to repress RAS-induced senescence, in a manner dependent upon MYC phosphorylation by CDK2 (35). These studies show that CDK2 activity is critical for circumventing senescence during MYC-induced transformation.…”

Section: Ink4amentioning

confidence: 60%

CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence—Implications for Therapeutic Intervention

Zalzali

Nasr

Harajly

et al. 2015

Molecular Cancer Research

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Cellular senescence, a form of cell-cycle arrest, is a tumorsuppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage-and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene-and DNA damage-induced cellular senescence, CDK2 transcript and protein are decreased in a p53-and RBdependent manner, and this repression is necessary for cell-cycle exit during senescence.Implications: These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors.

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“…8,105,106 For example, landmark studies demonstrated that transformation of primary murine cells with oncogenic Ras require its cooperative interaction with c-Myc. 107 Later findings revealed that activated c-Myc suppresses Ras-induced senescence, 108 whereas oncogenic Ras rescues cells from Myc-induced apoptosis. 8 Notably, the capacity of oncogenes to induce deregulated cell proliferation or promote Cellular senescence.…”

Section: Translational Control Of Cancer Genesismentioning

confidence: 99%

Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

Bitterman

Polunovsky²

2012

Cell Cycle

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Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation

Cited by 174 publications

References 45 publications

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

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

CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence—Implications for Therapeutic Intervention

Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

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