Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation

Bahram, Fuad; Tronnersjö, Susanna; Zakaria, Siti Mariam; Frings, Oliver; Fahlén, Sara; Nilsson, Helén; Goodwin, Jacob; Lehr, Natalie von der; Su, Yingtao; Lüscher, Bernhard; Castell, Alina; Larsson, Lars‐Gunnar

doi:10.18632/oncotarget.6693

Cited by 12 publications

(17 citation statements)

References 70 publications

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“…The latter is in part the result of an increase in MYC mRNA (Suppl. Figure S5(b)) and in part probably due to stabilization of the MYC protein, consistent with the increased phosphorylation of MYC at Ser 62 (P-MYC), which is known to be involved in activation and stabilization of MYC [13,34,[38][39][40][41][42][43]. As expected, DOX treatment also increased phosphorylation of the downstream effectors of RAS, ERK (P-ERK) and AKT (P-AKT) (Figure 4(f) and Suppl.…”

Section: Myc Dampens the Ras Pathway And Ras Does Not Support Myc Expsupporting

confidence: 78%

“…Since the effect of RAS on MYC gene expression is known to be mediated via activation of ERK [43,56], this reduction could therefore in part be due to the observed reduced ERK activity. Further, phosphorylation of MYC Ser-62 by ERK or CDKs has been shown to increase the activity and stability of the MYC protein [13,34,[38][39][40][41][42][43], suggesting that part of the reduced MYC expression may occur at the protein level. Ser-62 phosphorylation seems to be particularly important in survival and regeneration in response to DNA damage and for suppression of senescence [13,39,41,42].…”

Section: Discussionmentioning

confidence: 99%

“…Protein concentration was determined using Bradford assay (BioRad, 500-0006). Immunoprecipitation and immunoblot analyses were performed as described previously [38].…”

Section: Immunoprecipitation and Immunoblot Analysismentioning

confidence: 99%

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MYC and RAS are unable to cooperate in overcoming cellular senescence and apoptosis in normal human fibroblasts

et al. 2018

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The MYC and RAS oncogenes are sufficient for transformation of normal rodent cells. This cooperativity is at least in part based on suppression of RAS-induced cellular senescence by MYC and block of MYC-induced apoptosis by RAS – thereby canceling out two main barriers against tumor development. However, it remains unclear whether MYC and RAS cooperate in this way in human cells, where MYC and RAS are not sufficient for transformation. To address this question, we established a combined Tet-inducible H-RASV12 and hydroxytamoxifen-inducible MycER system in normal human BJ fibroblasts. We show here that activation of RAS alone induced senescence while activation of MYC alone or together with RAS triggered DNA damage, induction of p53 and massive apoptosis, suggesting that RAS cannot rescue MYC-induced apoptosis in this system. Although coexpression with MYC reduced certain RAS-induced senescence markers (histone H3 lysine 9 trimethylation and senescence-associated β-GAL activity), the induction of the senescence marker p16INK4A was further enhanced and the culture ceased to proliferate within a few days, revealing that MYC could not fully suppress RAS-induced senescence. Furthermore, depletion of p53, which enhanced proliferation and rescued the cells from RAS-induced senescence, did not abrogate MYC-induced apoptosis. We conclude that MYC and RAS are unable to cooperate in overcoming senescence and apoptosis in normal human fibroblasts even after depletion of p53, indicating that additional oncogenic events are required to abrogate these fail-safe mechanisms and pave the way for cellular transformation. These findings have implications for our understanding of the transformation process in human cells.Abbreviations and acronyms: CDK: Cyclin-dependent kinase; DDR: DNA damage response; DOX: Doxycycline; EdU: 5-ethynyl-2ʹ-deoxyuridine; FACS: Fluorescence Activated Cell Sorting; MycER: MYC-estrogen receptor; OHT: 4-hydroxytamoxifen; OIS: Oncogene-induced senescence; PP2A: Protein phosphatase 2A; ROS: Reactive oxygen species; SA-β-GAL: Senescence-associated β-galactosidase; SAHF: Senescence-associated heterochromatin foci; shRNA: Short hairpin RNA; YFP: Yellow fluorescent protein

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Section: Myc Dampens the Ras Pathway And Ras Does Not Support Myc Expsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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MYC and RAS are unable to cooperate in overcoming cellular senescence and apoptosis in normal human fibroblasts

et al. 2018

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“…IFN-γ has been shown to control tumor cell growth by cell cycle arrest through induction of cyclin dependent kinase inhibitors, such as p27Kip [23]. To clarify and confirm the effect of IFN-γ and poly I:C on cell cycle arrest and apoptosis, we collected cell lysates at 24 and 48h from a separate cohort of B16F10 cells stimulated with IFN-γ and poly I:C, and performed western blots for cleaved caspase-3, p27Kip, and ISG54.…”

Section: Resultsmentioning

confidence: 99%

Activation of IRF3 contributes to IFN-γ and ISG54 expression during the immune responses to B16F10 tumor growth

Guinn

Brown

Petro³

2017

International Immunopharmacology

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Interferon Regulatory Factor (IRF-3) has been shown to contribute to immune control of B16 melanoma tumor growth. We have shown previously that IRF-3 has a role in IFN-γ-induced expression of pro-apoptotic interferon stimulated gene 54 (ISG54) in macrophages and IFN-γ in T cells. To investigate the IRF3-IFN-γ-ISG54 nexus, we injected C57Bl/6 (B6) and IRF3KO mice s.c. with luciferase-producing B16-F10 tumor cells. Tumor growth as measured by luciferase levels was similar between B6 and IRF3KO mice at day 2 and 6, but was significantly greater at day 9 in IRF3KO mice compared with B6 mice. Transcription factor assays on splenic protein extracts after tumor inoculation revealed peak activation of IRF3 and IRF7 at day 6 in B6 tumor-bearing mice but not in IRF3KO tumor-bearing mice. Likewise, significant induction of IFN-γ occurred in spleens and tumors in B6 mice from day 6–9 but failed to occur in tumor-bearing IRF3KO mice. Previous reports from other labs showed that the anti-tumor properties of IFN-γ are the result of cell cycle arrest. Using B16F1 cells or B16F1 cells deficient in IFN-γ receptor (B16-IRFGRKO), we found that IFN-γ alone and in synergy with the TLR3/IRF3 agonists, poly I:C, decreased B16F1 cell growth in significant correlation with increased ISG54 expression. Moreover, IFN-γ alone increased expression of the cell cycle inhibitor, p27Kip while IFN-γ plus poly I:C increased cleaved Caspase-3 in B16 cells. Thus, it is likely that an IFN-γ/IRF3/ISG54 nexus can significantly contribute to tumor cell control during anti-tumor immune responses.

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“…Overall, many substrates are DNA-binding transcription factors, such as SMAD3, FOXM1, FOXO1, ID2, NFY, B-MYB and MYC [ 101 ], whereby CDK2 affects transcriptional output. Also other types of CDK2 substrates are reported including p27 [ 122 , 123 , 124 ] and the E3 ubiquitin ligase FBXO28 [ 9 ], both involved in MYC regulation [ 9 , 58 , 125 ] (see further below), the polycomb repressor protein EZH2 and the anti-apoptotic protein MCL1 [ 101 ].…”

Section: The Crosstalk Between Myc and Cdk2mentioning

confidence: 99%

MYC Modulation around the CDK2/p27/SKP2 Axis

Hydbring

Castell

Larsson

2017

Genes

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MYC is a pleiotropic transcription factor that controls a number of fundamental cellular processes required for the proliferation and survival of normal and malignant cells, including the cell cycle. MYC interacts with several central cell cycle regulators that control the balance between cell cycle progression and temporary or permanent cell cycle arrest (cellular senescence). Among these are the cyclin E/A/cyclin-dependent kinase 2 (CDK2) complexes, the CDK inhibitor p27KIP1 (p27) and the E3 ubiquitin ligase component S-phase kinase-associated protein 2 (SKP2), which control each other by forming a triangular network. MYC is engaged in bidirectional crosstalk with each of these players; while MYC regulates their expression and/or activity, these factors in turn modulate MYC through protein interactions and post-translational modifications including phosphorylation and ubiquitylation, impacting on MYC’s transcriptional output on genes involved in cell cycle progression and senescence. Here we elaborate on these network interactions with MYC and their impact on transcription, cell cycle, replication and stress signaling, and on the role of other players interconnected to this network, such as CDK1, the retinoblastoma protein (pRB), protein phosphatase 2A (PP2A), the F-box proteins FBXW7 and FBXO28, the RAS oncoprotein and the ubiquitin/proteasome system. Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment.

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Interferon-γ-induced p27KIP1 binds to and targets MYC for proteasome-mediated degradation

Cited by 12 publications

References 70 publications

MYC and RAS are unable to cooperate in overcoming cellular senescence and apoptosis in normal human fibroblasts

MYC and RAS are unable to cooperate in overcoming cellular senescence and apoptosis in normal human fibroblasts

Activation of IRF3 contributes to IFN-γ and ISG54 expression during the immune responses to B16F10 tumor growth

MYC Modulation around the CDK2/p27/SKP2 Axis

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