Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53

Senturk, J C; Bohlman, Stephen; Manfredi, James J.

doi:10.1038/onc.2017.229

Cited by 14 publications

(16 citation statements)

References 53 publications

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“…Above all, the cascade might be MDM2 negatively regulated PKA, PKA positively regulated H1.4 S35ph , which was negatively modulated by Ras G12V/Y40 -PI3K/AKT. This result stands by the conclusion that MDM2 was upregulated in osteosarcoma [34]. Our result provides an explanation to connect Ras G12V/Y40 -PI3K/AKT with MDM2 and further with H1.4 S35ph .…”

Section: R E T R a C T E Dsupporting

confidence: 74%

RETRACTED ARTICLE: K-Ras ^G12V/Y40C -PI3K/AKT pathway regulates H1.4 ^S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

Zhang

Liu

Dong

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Background: Osteosarcoma is prevalent in children and adolescents. H1.4 modification is involved in various types of cancers. Ras pathway is often activated in human cancers. Herein, we explored the effects of Ras pathway through H1.4 S35ph. Methods: Osteosarcoma cancer cell line MG-63 was transfected with Ras gene with G12V and Y40C site mutation. The phosphorylation of H1.4 S35 and AKT was detected by Western blot. Cell viability, cell colonies and migration were analyzed by MTT assay, soft-agar colony formation assay and Transwell assay, respectively. The expression of Ras pathway downstream factors and PKA was detected by qRT-PCR. The relationship between Ras and downstream factors was detected by ChIP. The cell cycle progression was measured by flow cytometry. Results: Transfection with Ras G12V/Y40C decreased H1.4 S35ph expression while switched on p-AKT Ser473. Ras G12V/Y40C increased cell viability, colony numbers and migration while H1.4 S35E (H1.4 S35ph overexpression) led to the opposite results. The regulation of Ras G12V/Y40C and H1.4 S35E on Ras downstream factors was contrary to each other. Results demonstrated a positive relationship between PKA with H1.4 S35ph with Ras G12V/Y40C down-regulated both. However, PKA and MDM2 revealed negative regulation with Ras G12V/Y40C transfection up-regulated MDM2. Conclusion: Ras G12V/Y40C-PI3K/AKT signal pathway decreased H1.4 S35ph through down-regulation of PKA while up-regulation of MDM2 in MG-63 cells. HIGHLIGHTS 1. H1.4 S35ph is regulated by K-Ras G12V/Y40-PI3K/AKT in MG-63 cells; 2. Overexpression of H1.4 S35ph regulates MG-63 cell growth; 3. H1.4 S35ph regulates Ras downstream factors; 4. K-Ras G12V/Y40C-PI3K/AKT activity induces PKA degradation to down-regulate H1.4 S35ph ; 5. K-Ras G12V/Y40C-PI3K/AKT activity involves in PKA degradation via MDM2.

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Section: R E T R a C T E Dsupporting

confidence: 74%

RETRACTED ARTICLE: K-Ras ^G12V/Y40C -PI3K/AKT pathway regulates H1.4 ^S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

Zhang

Liu

Dong

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Introduction or removal of ubiquitin is also a mechanism of drug resistance, as it modulates the Top2a activities and protein levels through proteasome degradation [53][54][55] . Deficiency in the RNF168 E3 ubiquitin ligase in breast cancer cells, or elevated levels of ubiquitin ligase Mdm2 in osteosarcoma cells, confers resistance to the Top2 poison etoposide, by regulating Top2 activities [53,56] . Ubiquitin-mediated degradation of Top2 also contributes to the level of drug resistance in solid tumors since proteasome inhibition leads to etoposide resistance [57] .…”

Section: Ubiquitinations and Sumoylationsmentioning

confidence: 99%

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

Lotz¹,

Lamour²

2020

CDR

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The type 2 DNA topoisomerases (Top2) are conserved enzymes and biomarkers for cell proliferation. The catalytic activities of the human isoform Top2a are essential for the regulation of DNA topology during DNA replication, transcription, and chromosome segregation. Top2a is a prominent target for anti-cancer drugs and is highly regulated by post-translational modifications (PTM). Despite an increasing number of proteomic studies, the extent of PTM in cancer cells and its importance in drug response remains largely uncharacterized. In this review, we highlight the different modifications affecting the human Top2a in healthy and cancer cells, taking advantage of the structure-function information accumulated in the past decades. We also overview the regulation of Top2a by PTM, the level of PTM in cancer cells, and the resistance to therapeutic compounds targeting the Top2 enzyme. Altogether, this review underlines the importance of future studies addressing more systematically the interplay between PTM and Top2 drug resistance.

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“…Doxorubicin, a standard systemic treatment in DDLPS, induces DNA damage and leads to p53‐mediated apoptosis . Previous research suggests that p53 activity is critical for doxorubicin‐induced DNA damage response and apoptosis in multiple malignancies . Better understanding of the MDM2:p53 axis in DDLPS may lead to better treatment selection for these patients.…”

Section: Introductionmentioning

confidence: 99%

Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

et al. 2019

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Background Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 (MDM2) is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of MDM2 amplification, not simply the presence of MDM2 amplification, may be biologically important to the actions of DDLPS. Patients and Methods The distribution of MDM2 amplification in DDLPS was assessed using data from a commercial sequencing laboratory (n = 642) and The Cancer Genome Atlas (n = 57). Data from two retrospective clinical trials (n = 15, n = 16) and one prospective clinical trial (n = 25) were used to test MDM2’s utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines. Results Genomic MDM2 amplification follows a highly reproducible log‐normal distribution. In patients with DDLPS treated with complete tumor resection, elevated MDM2 was associated with shortened time to recurrence as measured by genomic amplification (p = .003) and mRNA expression (p = .04). In patients requiring systemic therapy, higher MDM2 amplification was associated with reduced overall survival (p = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline MDM2 levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity. Conclusion MDM2 amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of MDM2 as a predictive biomarker in DDLPS is warranted. Implications for Practice No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 (MDM2) is currently used for diagnosis, the clinical relevance of MDM2 amplification has yet to be fully assessed. This study found that MDM2 amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that MDM2 amplification may be a useful biomarker in DDLPS.

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Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53

Cited by 14 publications

References 53 publications

RETRACTED ARTICLE: K-Ras ^G12V/Y40C -PI3K/AKT pathway regulates H1.4 ^S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

RETRACTED ARTICLE: K-Ras ^G12V/Y40C -PI3K/AKT pathway regulates H1.4 ^S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

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Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53

Cited by 14 publications

References 53 publications

RETRACTED ARTICLE: K-Ras G12V/Y40C -PI3K/AKT pathway regulates H1.4 S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

RETRACTED ARTICLE: K-Ras G12V/Y40C -PI3K/AKT pathway regulates H1.4 S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

The interplay between DNA topoisomerase 2α post-translational modifications and drug resistance

Degree of MDM2 Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma

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Product

Resources

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RETRACTED ARTICLE: K-Ras ^G12V/Y40C -PI3K/AKT pathway regulates H1.4 ^S35ph through PKA to promote the occurrence and development of osteosarcoma cancer

RETRACTED ARTICLE: K-Ras ^G12V/Y40C -PI3K/AKT pathway regulates H1.4 ^S35ph through PKA to promote the occurrence and development of osteosarcoma cancer