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Article: Mdm2 in the response to radiation.

Perry, Mary Ellen

2004 Volume 2, Issue 1, Page(s) 9–19

Abstract: ... by p53 in the radiation response. Increased levels of Mdm2 appear to ensure that the activity of p53 ... UV radiation. The level of Mdm2 expression determines the extent to which radiation induces an increase ... to ionizing radiation. Thus, Mdm2 is a potential target for therapeutic intervention because its inhibition ...

Abstract	Murine double minute 2 (Mdm2) is a critical component of the responses to both ionizing and UV radiation. The level of Mdm2 expression determines the extent to which radiation induces an increase in the activity of the p53 tumor suppressor. Mdm2 acts as a survival factor in many cell types by limiting the apoptotic function of p53. In addition, expression of mdm2 is induced in response to DNA damage, and the resulting high levels of Mdm2 protein are thought to shorten the length of the cell cycle arrest established by p53 in the radiation response. Increased levels of Mdm2 appear to ensure that the activity of p53 returns to its low basal levels in surviving cells. Decreased levels of Mdm2 sensitize cells to ionizing radiation. Thus, Mdm2 is a potential target for therapeutic intervention because its inhibition may radiosensitize the subset of human tumors expressing wild-type p53 such that radiotherapy is more efficacious.
MeSH term(s)	Animals ; Apoptosis ; Cell Cycle ; Gene Expression Regulation, Neoplastic/radiation effects ; Humans ; Neoplasms/metabolism ; Neoplasms/radiotherapy ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2 ; Radiation, Ionizing ; Tumor Cells, Cultured/radiation effects ; Tumor Suppressor Protein p53/metabolism ; Ultraviolet Rays
Chemical Substances	Nuclear Proteins ; Proto-Oncogene Proteins ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2004-01
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
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Article ; Online: hCINAP alleviates senescence by regulating MDM2 via p14ARF and the HDAC1/CoREST complex.

Huang, Xinping / Zhao, Yan / Wei, Min / Zhuge, Ruipeng / Zheng, Xiaofeng

Journal of molecular cell biology

2023 Volume 15, Issue 2

Abstract: ... senescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation ... signal response network. Identification of novel regulators of cellular senescence and elucidation ... induced senescence. Mechanistically, hCINAP functions through regulating MDM2 status by distinct ...

Abstract	Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network. Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discovery of new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPase protein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditis elegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulated senescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence. Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On the one hand, hCINAP decreases p53 stability by attenuating the interaction between p14ARF and MDM2; on the other hand, hCINAP promotes MDM2 transcription via inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively, our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlying the aging process.
MeSH term(s)	Mice ; Animals ; Humans ; Tumor Suppressor Protein p14ARF/metabolism ; Adenosine Triphosphatases/metabolism ; Cell Nucleus/metabolism ; Aging ; Cellular Senescence ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/metabolism ; Histone Deacetylase 1/metabolism
Chemical Substances	Tumor Suppressor Protein p14ARF ; Adenosine Triphosphatases (EC 3.6.1.-) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; HDAC1 protein, human (EC 3.5.1.98) ; Histone Deacetylase 1 (EC 3.5.1.98)
Language	English
Publishing date	2023-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2500949-7
ISSN	1759-4685 ; 1759-4685
ISSN (online)	1759-4685
ISSN	1759-4685
DOI	10.1093/jmcb/mjad015
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Article ; Online: Oscillatory Dynamics of p53-Mdm2 Circuit in Response to DNA Damage Caused by Ionizing Radiation.

Zhang, Yuan / Liu, Haihong / Li, Zhouhong / Miao, Zhonghua / Zhou, Jin

IEEE/ACM transactions on computational biology and bioinformatics

2019 Volume 17, Issue 5, Page(s) 1703–1713

Abstract: ... interaction in response to DNA damage following ionizing radiation (IR). We showed that a sufficient amount ... Although the dynamical behavior of the p53-Mdm2 loop has been extensively studied ... we developed an integrated model with five basic components and three ubiquitous time delays for the p53-Mdm2 ...

Abstract	Although the dynamical behavior of the p53-Mdm2 loop has been extensively studied, the understanding of the mechanism underlying the regulation of this pathway still remains limited. Herein, we developed an integrated model with five basic components and three ubiquitous time delays for the p53-Mdm2 interaction in response to DNA damage following ionizing radiation (IR). We showed that a sufficient amount of activated ATM level can initiate the p53 oscillations with nearly the same amplitude over a wide range of the ATM level; a proper range of p53 level is also required for generating the oscillations, for too high or too low levels it would fail to generate the oscillations; and increased Mdm2 level leads to decreased amplitude of the p53 oscillation and reduced expression of the p53 activity. Moreover, we found that the negative feedback loop formed between p53 and nuclear Mdm2 plays a dominant role in determining the p53 dynamics, whereas when interaction strength of the negative feedback loop becomes weaker, the positive feedback loop formed between p53 and cytoplasmatic Mdm2 can induce different types of dynamics. Furthermore, we demonstrated that the total time delay required for protein production and nuclear translocation of Mdm2 can induce p53 oscillations even when the p53 level is at a certain stable high steady state or at a certain stable low steady state. In addition, the two important features of the oscillatory dynamics-amplitude and period-can be controlled by such time delay. These results are in agreement with multiple experimental observations and may enrich our understanding of the dynamics of the p53 network.
MeSH term(s)	Computational Biology ; DNA Damage/radiation effects ; Models, Biological ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Radiation, Ionizing ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2019-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1557-9964
ISSN (online)	1557-9964
DOI	10.1109/TCBB.2019.2899574
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Article: Pinning Control for the p53-Mdm2 Network Dynamics Regulated by p14ARF.

Suarez, Oscar J / Vega, Carlos J / Sanchez, Edgar N / González-Santiago, Ana E / Rodríguez-Jorge, Otoniel / Alanis, Alma Y / Chen, Guanrong / Hernandez-Vargas, Esteban A

Frontiers in physiology

2020 Volume 11, Page(s) 976

Abstract: ... For the first case, the oscillatory pattern under gamma-radiation is recovered; afterward, as the second case ... p53 regulates the cellular response to genotoxic damage and prevents carcinogenic events ... Theoretical and experimental studies state that the p53-Mdm2 network constitutes the core module of regulatory ...

Abstract	p53 regulates the cellular response to genotoxic damage and prevents carcinogenic events. Theoretical and experimental studies state that the p53-Mdm2 network constitutes the core module of regulatory interactions activated by cellular stress induced by a variety of signaling pathways. In this paper, a strategy to control the p53-Mdm2 network regulated by p14ARF is developed, based on the pinning control technique, which consists into applying local feedback controllers to a small number of nodes (pinned ones) in the network. Pinned nodes are selected on the basis of their importance level in a topological hierarchy, their degree of connectivity within the network, and the biological role they perform. In this paper, two cases are considered. For the first case, the oscillatory pattern under gamma-radiation is recovered; afterward, as the second case, increased expression of p53 level is taken into account. For both cases, the control law is applied to p14ARF (pinned node based on a virtual leader methodology), and overexpressed Mdm2-mediated p53 degradation condition is considered as carcinogenic initial behavior. The approach in this paper uses a computational algorithm, which opens an alternative path to understand the cellular responses to stress, doing it possible to model and control the gene regulatory network dynamics in two different biological contexts. As the main result of the proposed control technique, the two mentioned desired behaviors are obtained.
Language	English
Publishing date	2020-08-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2020.00976
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Article ; Online: Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis.

Chibaya, Loretah / Karim, Baktiar / Zhang, Hong / Jones, Stephen N

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 4

Abstract: ... of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 ... by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage ... We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling ...

Abstract	We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote Kras
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis/radiation effects ; Carcinogenesis/drug effects ; Carcinogenesis/genetics ; Carcinogenesis/radiation effects ; Carcinogens/toxicity ; Carcinoma, Hepatocellular/chemically induced ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/virology ; Cell Proliferation/genetics ; Cellular Senescence/drug effects ; Cellular Senescence/radiation effects ; DNA Damage/genetics ; DNA Damage/radiation effects ; Disease Models, Animal ; Humans ; Liver Neoplasms/chemically induced ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Liver Neoplasms/virology ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Mice ; Neoplasms, Radiation-Induced/genetics ; Neoplasms, Radiation-Induced/pathology ; Oxidative Stress/drug effects ; Oxidative Stress/radiation effects ; Papillomaviridae/pathogenicity ; Phosphorylation/drug effects ; Phosphorylation/radiation effects ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Radiation, Ionizing ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Carcinogens ; Reactive Oxygen Species ; Trp53 protein, mouse ; Tumor Suppressor Protein p53 ; Mdm2 protein, mouse (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Hras protein, mouse (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2021-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2003193118
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Article ; Online: Small Molecule Inhibition of MDM2-p53 Interaction Augments Radiation Response in Human Tumors.

Werner, Lauryn R / Huang, Shyhmin / Francis, David M / Armstrong, Eric A / Ma, Fang / Li, Chunrong / Iyer, Gopal / Canon, Jude / Harari, Paul M

Molecular cancer therapeutics

2015 Volume 14, Issue 9, Page(s) 1994–2003

Abstract: ... of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG ... to augment radiation response across a variety of tumor types harboring functional p53. ... MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is ...

Abstract	MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.
MeSH term(s)	Acetates/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Apoptosis/radiation effects ; Autophagy/drug effects ; Autophagy/radiation effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cell Survival/radiation effects ; Cellular Senescence/drug effects ; Cellular Senescence/radiation effects ; Disease Models, Animal ; Humans ; Mice ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/radiotherapy ; Piperidones/pharmacology ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Radiation Tolerance/drug effects ; Radiation, Ionizing ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid ; Acetates ; Antineoplastic Agents ; Piperidones ; Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2015-07-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-14-1056-T
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Zs.A 5750: Show issues

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Article ; Online: TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation.

Drummond, Catherine J / Esfandiari, Arman / Liu, Junfeng / Lu, Xiaohong / Hutton, Claire / Jackson, Jennifer / Bennaceur, Karim / Xu, Qing / Makimanejavali, Aditya Rao / Del Bello, Fabio / Piergentili, Alessandro / Newell, David R / Hardcastle, Ian R / Griffin, Roger J / Lunec, John

Oncotarget

2016 Volume 7, Issue 29, Page(s) 46203–46218

Abstract: ... remained sensitive to ionizing radiation (IR). These results indicate that MDM2/p53 binding antagonists ... by Nutlin-3, MI-63 or ionizing radiation was not observed in either the SJSA-1 or the NGP derived cell lines ... Non-genotoxic reactivation of the p53 pathway by MDM2-p53 binding antagonists is an attractive ...

Abstract	Non-genotoxic reactivation of the p53 pathway by MDM2-p53 binding antagonists is an attractive treatment strategy for wild-type TP53 cancers. To determine how resistance to MDM2/p53 binding antagonists might develop, SJSA-1 and NGP cells were exposed to growth inhibitory concentrations of chemically distinct MDM2 inhibitors, Nutlin-3 and MI-63, and clonal resistant cell lines generated. The p53 mediated responses of parental and resistant cell lines were compared. In contrast to the parental cell lines, p53 activation by Nutlin-3, MI-63 or ionizing radiation was not observed in either the SJSA-1 or the NGP derived cell lines. An identical TP53 mutation was subsequently identified in both of the SJSA-1 resistant lines, whilst one out of three identified mutations was common to both NGP derived lines. Mutation specific PCR revealed these mutations were present in parental SJSA-1 and NGP cell populations at a low frequency. Despite cross-resistance to a broad panel of MDM2/p53 binding antagonists, these MDM2-amplified and TP53 mutant cell lines remained sensitive to ionizing radiation (IR). These results indicate that MDM2/p53 binding antagonists will select for p53 mutations present in tumours at a low frequency at diagnosis, leading to resistance, but such tumours may nevertheless remain responsive to alternative therapies, including IR.
Language	English
Publishing date	2016-07-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.10073
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Article: Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis.

Carr, Michael I / Jones, Stephen N

Translational cancer research

2017 Volume 5, Issue 6, Page(s) 707–724

Abstract: ... ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily ... as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response ... s) of p53 in the DNA damage response and in tumor suppression, and how ...

Abstract	The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function. Although regulation of p53 levels and function is coordinated by many proteins, it is now widely accepted that the master regulator of p53 is Mdm2. In this review, we discuss the role(s) of p53 in the DNA damage response and in tumor suppression, and how post-translational modification of Mdm2 regulates the Mdm2-p53 signaling axis to govern p53 activities in the cell.
Language	English
Publishing date	2017-07-08
Publishing country	China
Document type	Journal Article
ZDB-ID	2901601-0
ISSN	2219-6803 ; 2218-676X
ISSN (online)	2219-6803
ISSN	2218-676X
DOI	10.21037/tcr.2016.11.75
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Article ; Online: A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma.

Yi, Hanjie / Yan, Xianglei / Luo, Qiuyun / Yuan, Luping / Li, Baoxia / Pan, Wentao / Zhang, Lin / Chen, Haibo / Wang, Jing / Zhang, Yubin / Zhai, Yifan / Qiu, Miao-Zhen / Yang, Da-Jun

Journal of experimental & clinical cancer research : CR

2018 Volume 37, Issue 1, Page(s) 97

Abstract: ... on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much ... adenocarcinoma. MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage which leads ... Background: Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone ...

Abstract	Background: Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone or combined with chemotherapy plays important role in locally advanced and metastatic gastric adenocarcinoma. MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage which leads to cell cycle arrest and apoptosis. Therefore, restoring p53 function by inhibiting its interaction with MDM2 is a promising therapeutic strategy for cancer. APG-115 is a novel small molecule inhibitor which blocks the interaction of MDM2 and p53. In this study, we investigated that the radiosensitivity of APG-115 in gastric adenocarcinoma in vitro and in vivo. Methods: The role of APG-115 in six gastric cancer cells viability in vitro was determined by CCK-8 assay. The expression level of MDM2, p21, PUMA and BAX in AGS and MKN45 cell lines was measured via real-time PCR (RT-PCR). The function of treatment groups on cell cycle and cell apoptosis were detected through Flow Cytometry assay. Clonogenic assays were used to measure the radiosensitivity of APG-115 in p53 wild type gastric cancer cell lines. Western blot was conducted to detect the protein expressions of mdm2-p53 signal pathway. Xenograft models in nude mice were established to explore the radiosensitivity role of APG-115 in gastric cancer cells in vivo. Results: We found that radiosensitization by APG-115 occurred in p53 wild-type gastric cancer cells. Increasing apoptosis and cell cycle arrest was observed after administration of APG-115 and radiation. Radiosensitivity of APG-115 was mainly dependent on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much more significantly than either single treatment. Moreover, the number of proliferating cells (Ki-67) significantly decreased in combination group compared with single treatment group. Conclusions: In summary, we found that combination of MDM2-p53 inhibitor (APG-115) and radiotherapy can enhance antitumor effect both in vitro and in vivo. This is the first report on radiosensitivity of APG-115 which shed light on clinical trial of the combination therapy of radiation with APG-115 in gastric adenocarcinoma.
MeSH term(s)	Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Animals ; Apoptosis ; Humans ; Mice ; Mice, Nude ; Proto-Oncogene Proteins c-mdm2/metabolism ; Radiation Tolerance ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/pathology ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2018-05-02
Publishing country	England
Document type	Journal Article
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-018-0765-8
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Article ; Online: MDM2 Inhibition in a Subset of Sarcoma Cell Lines Increases Susceptibility to Radiation Therapy by Inducing Senescence in the Polyploid Cells

Samayita Das, PhD

Advances in Radiation Oncology, Vol 5, Iss , Pp 33-

2020 Volume 42

Abstract: ... Removal of MDM2 inhibitor (with or without radiation therapy) led to the emergence of ploidy-based ... of the p53-MDM2-p21 signaling axis in response to combination therapy in all cell lines with wild-type TP53 ... p53. Radiation therapy is an integral component for treating liposarcoma and induces p53. Based ...

Abstract	Purpose: Inhibition of p53 by amplification of MDM2 is one of the key contributors in the oncogenesis of a subset of soft tissue sarcoma (STS) known as well-/dedifferentiated liposarcoma. A small molecule MDM2 antagonist, nutlin-3, induces the p53 pathway by disrupting the interaction between MDM2 and p53. Radiation therapy is an integral component for treating liposarcoma and induces p53. Based on wild-type TP53 status in liposarcoma, it was investigated whether MDM2 inhibition with irradiation led to enhanced reactivation of p53 and subsequent p53-mediated effects in liposarcoma. Methods and Materials: Clonogenic assays, immunoblotting, flow cytometry/fluorescence-activated cell sorting, and senescence assays were employed in liposarcoma cell lines after co-treatment with nutlin-3 and radiation. Results: Upon treatment with nutlin-3, 2 of the well-/dedifferentiated liposarcoma (MDM2Amp/TP53WT) cell lines displayed radiosensitivity with sensitization enhancement ratio values of >1. In contrast, the cell line with mutant TP53 showed sensitization enhancement ratio values of ∼1. Immunoblotting revealed induced reactivation of the p53-MDM2-p21 signaling axis in response to combination therapy in all cell lines with wild-type TP53. Removal of MDM2 inhibitor (with or without radiation therapy) led to the emergence of ploidy-based heterogeneous subpopulations (4N and >4N) in TP53 wild-type cells and not in TP53 mutant cells. Immunoblotting of cell cycle markers (G1, G2/M) revealed the generation of 4N G1 cells. Sorting and long-term fate analysis of different populations (2N, 4N, and >4N) by colony assay displayed attenuated colony-forming potential and augmented senescence of the 4N and >4N cells contributing to the radiosensitization effect. Conclusions: Nutlin-3 increases the vulnerability of liposarcoma cell lines to radiation by augmented activation of p53. The cells underwent senescence. Presence and activation of p53 are required for exertion of the radiosensitizing effect by nutlin-3, but this is ...
Keywords	Medical physics. Medical radiology. Nuclear medicine ; R895-920 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	616
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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