c-Myc Proteolysis by the Ubiquitin-Proteasome Pathway: Stabilization of c-Myc in Burkitt's Lymphoma Cells

Gregory, Mark A.; Hann, Stephan

doi:10.1128/mcb.20.7.2423-2435.2000

Cited by 420 publications

(353 citation statements)

References 73 publications

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“…In order to estimate the change in c-MYC protein stability induced by UV-light, cells were irradiated in the presence of the protein synthesis inhibitor cycloheximide. Whereas c-MYC halflife was about 30 min in unirradiated cells, in agreement with the literature, 14 it dropped dramatically (<15 min) after UV-irradiation (Fig. 2C).…”

Section: Resultssupporting

confidence: 80%

“…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%

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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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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

c-Myc protein is degraded in response to UV irradiation

Britton¹,

Salles²,

Calsou³

2008

Cell Cycle

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“…27,28 These mutations prevent phosphorylation at Threonine 58 and result in stabilized c-Myc protein in certain Burkitt's lymphoma cells. 19,29,30 Whether stabilization of c-Myc occurs in other human hematopoietic malignancies has not previously been reported.…”

Section: Introductionmentioning

confidence: 99%

Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias

et al. 2006

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Overexpression of the c-Myc oncoprotein is observed in a large number of hematopoietic malignancies, and transgenic animal models have revealed a potent role for c-Myc in the generation of leukemias and lymphomas. However, the reason for high c-Myc protein levels in most cases is unknown. We examined whether aberrant protein stabilization could be a mechanism of c-Myc overexpression in leukemia cell lines and in primary bone marrow samples from pediatric acute lymphoblastic leukemia (ALL) patients. We found that c-Myc protein half-life was prolonged in the majority of leukemia cell lines and bone marrow samples tested. There were no mutations in the c-myc gene in any of the leukemia cell lines that could account for increased c-Myc stability. However, abnormal phosphorylation at two conserved sites, Threonine 58 and Serine 62, was observed in leukemia cell lines with stabilized c-Myc. Moreover, stabilized c-Myc from the ALL cell lines showed decreased affinity for glycogen synthase kinase3b, the kinase that phosphorylates c-Myc at Threonine 58 and facilitates its degradation. These findings reveal that deregulation of the c-Myc degradation pathway controlled by Serine 62 and Threonine 58 phosphorylation is a novel mechanism for increased expression of a potent oncoprotein known to be involved in hematopoietic malignancies.

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“…BC-1, BC-3, BC-5 and BCBL-1 cells were treated with a protein synthesis inhibitor, cycloheximide and c-Myc degradation was monitored using immunoblot analysis. BL cell lines Daudi and JD38 were previously reported to have a normal and a prolonged half-life of c-Myc, respectively (Gregory and Hann, 2000), and were used as a negative and a positive control. Figure 1 shows that the steady-state level of c-Myc declined rapidly at 30 min in Daudi as reported, but decayed at a much slower pace in the PEL cell lines.…”

Section: C-myc Is Stabilized In Pel Cell Linesmentioning

confidence: 99%

“…These phosphorylation events take place in an orderly manner during the G1 stage of the cell cycle through the stimulation of Ras by growth factors and its activation of the Raf-MAPK/ ERK kinase-extracellular signal-regulated kinase and phosphatidylinositol 3 0 -kinase/Akt pathways. Phosphorylation of c-Myc on S62 is necessary for its phosphorylation by glycogen synthase kinase-3b (GSK-3b) on T58, which is crucial for c-Myc degradation in late G1 (Gregory and Hann, 2000;Sears et al, 2000). Subsequent dephosphorylation of S62 by protein phosphatase 2A (PP2A), is required for a proper recognition of c-Myc by the proteasomal machinery (Yeh et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen

2007

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Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin's lymphoma, which is associated with infection by Kaposi's sarcoma herpesvirus (KSHV)/human herpesvirus-8. The c-Myc transcription factor plays an important role in cellular proliferation, differentiation and apoptosis. Lymphomas frequently have deregulated c-Myc expression owing to chromosomal translocations, amplifications or abnormal stabilization. However, no structural abnormalities were found in the c-myc oncogene in PEL. Given that c-Myc is often involved in lymphomagenesis, we hypothesized that it is deregulated in PEL. We report that PEL cells have abnormally stable c-Myc protein. The turnover of c-Myc protein is stringently regulated by post-transcriptional modifications, including phosphorylation of c-Myc threonine 58 (T58) by glycogen synthase kinase-3b (GSK-3b). Our data show that the impaired c-Myc degradation in PEL cells is associated with a significant underphosphorylation of c-Myc T58. The KSHV latency-associated nuclear antigen (LANA) is responsible for this deregulation. Overexpression of LANA in human embryonic kidney 293 or peripheral blood B cells leads to post-transcriptional deregulation of c-Myc protein. Conversely, when LANA is eliminated from PEL cells using RNA interference, GSK-3b-mediated c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3b-containing complexes in PEL cells further confirms the significance of these interactions in naturally KSHV-infected cells.

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c-Myc Proteolysis by the Ubiquitin-Proteasome Pathway: Stabilization of c-Myc in Burkitt's Lymphoma Cells

Cited by 420 publications

References 73 publications

c-Myc protein is degraded in response to UV irradiation

c-Myc protein is degraded in response to UV irradiation

Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias

Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen

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