Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias

Malempati, Suman; Tibbitts, Deanne; Cunningham, Melissa A.; Akkari, Yassmine; Olson, Susan B.; Fan, Guang; Sears, Rosalie C.

doi:10.1038/sj.leu.2404317

Cited by 81 publications

(97 citation statements)

References 45 publications

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“…We analyzed the turnover rate of Myc protein in these cell lines plus three additional breast cancer cell lines and an additional control cell line, human mammary epithelial cells immortalized with hTERT (hMEChTERT). Myc half-life was significantly longer in all eight breast cancer cell lines, ranging from 34 to 90 min, compared with Myc in the controls, which ranged from 16 to 20 min, consistent with a variety of other nontransformed proliferating cell types (25,26) ( Fig. 1 A-C and Fig.…”

Section: Myc Protein Stability Is Increased In Breast Cancer Cell Linsupporting

confidence: 77%

“…We then investigated whether dysfunction of the Myc degradation pathway involving T58 and S62 phosphorylation could account for the increased Myc stability. As part of this pathway, in normal cells, Myc is dephosphorylated at S62 soon after T58 is phosphorylated, leading to rapid Myc turnover and an overall relatively low level of pS62 and high level of pT58 (14,25). In contrast, deregulation of this degradation pathway leads to an overall high level of pS62 and low level of pT58.…”

Section: Myc Protein Stability Is Increased In Breast Cancer Cell Linmentioning

confidence: 99%

“…In contrast, deregulation of this degradation pathway leads to an overall high level of pS62 and low level of pT58. We examined phosphorylation at T58 and S62 by using phospho-specific antibodies (24,25,27) (Fig. S2A).…”

Section: Myc Protein Stability Is Increased In Breast Cancer Cell Linmentioning

confidence: 99%

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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: Myc Protein Stability Is Increased In Breast Cancer Cell Linsupporting

confidence: 77%

Section: Myc Protein Stability Is Increased In Breast Cancer Cell Linmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Cells were lysed as described (22). Equal amounts of proteins were loaded and separated by SDS-PAGE, transferred to polyvinylidene fluoride membranes, and detected by immunoblotting with the SuperECL Plus Detection Reagent (Applygen) or the ECL Advance Detection Kit (GE Healthcare).…”

Section: Western Blot Analysismentioning

confidence: 99%

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

Huang

Weng

Wang

et al. 2012

Molecular Cancer Therapeutics

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The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitinproteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment.

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“…10 The half-life of c-MYC is very short in quiescent cells due to ubiquitin-mediated proteolysis; 11,12 in contrast, c-MYC accumulates by post-translational stabilization upon stimulation into the cell cycle. 13 In cancer cells, c-MYC is often overexpressed due either to increase of the transciption rate, to point mutations in the gene, 11,14,15 to aberrant phosphorylation patterns on the N-terminal phosphorylated sites driving protein degradation 16 or, as shown very recently, to high expression of an ubiquitin-specific protease. 17 This upregulation of c-MYC generates DNA damage and promotes genomic instability, [18][19][20] probably favoring the selection of cells with disabled checkpoints.…”

Section: Introductionmentioning

confidence: 99%

c-Myc protein is degraded in response to UV irradiation

Britton¹,

Salles²,

Calsou³

2008

Cell Cycle

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The c-MYC proto-oncogene encodes a transcription factor that is critical for cell growth and proliferation. It is one of the genes frequently altered in cancer cells in which it exhibits constitutive activity. The half-life of c-MYC is very short in quiescent cells due to ubiquitin-mediated proteolysis. We report here the rapid and dose-dependent decline of c-MYC protein level after UV-irradiation in various human and rodent cells. This decline is due to a proteasomal degradation of c-MYC protein and does not require the binding sites for the FBW7 and SKP2 ubiquitin ligases. Together, our data exclude a prominent role for the stress-responsive kinase PAK2, for the major phosphoinositide 3-kinase related protein kinases ATR, ATM, DNA-PK and mTOR and for ERK, JNK and p38 mitogen activated protein kinases in this UV-induced degradation process. We propose that c-MYC degradation is part of the global cell response to UV-damage, complementary to the accumulation and activation of the p53 transcription factor. By contributing to the replication arrest after infliction of lesions to the genome, the induced degradation of c-MYC may be part of the safeguard mechanisms maintaining genome stability.

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Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias

Cited by 81 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

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

c-Myc protein is degraded in response to UV irradiation

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