The Role of MDM2 Amplification and Overexpression in Tumorigenesis

Oliner, Jonathan D.; Saiki, Anne Y.; Caenepeel, Sean

doi:10.1101/cshperspect.a026336

Cited by 189 publications

(141 citation statements)

References 79 publications

(95 reference statements)

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“…20 MDM2 gene amplification has been observed in numerous cancers, resulting in a loss of p53-dependent activities such as apoptosis and cell-cycle arrest. 21 We suspect that overexpression of MDM2 in OSA 1777 may function to inactivate p53 and therefore promote its tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Recurrent Osteosarcoma Cell Line: OSA 1777

Thanindratarn

Dean

et al. 2019

Journal Orthopaedic Research

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Osteosarcoma (OSA) is the most common primary bone malignancy overall and is responsible for considerable adolescent mortality. Approximately 850 patients are newly diagnosed with OSA in the United States each year. While the 5‐year survival rate for localized OSA has improved from <20% over 40 years ago to over 65% today, progress has dwindled over the past three decades. Therapeutic stagnation has occurred, in part, as a result of limited preclinical models and the overall heterogeneity of OSA among patients. In this study, we report the establishment and characterization of a novel OSA cell line: OSA 1777. This cell line was isolated from the recurrent tumor specimen of a 19‐year‐old female who initially experienced 99% tumor necrosis after neoadjuvant chemotherapy and eventually had local recurrence and metastases. We present OSA 1777 growth characteristics, tumor markers, chemotherapeutic sensitivities, and oncogenic spheroid formation. In a two‐dimensional (2D) monolayer culture, OSA 1777 exhibited a spindle shape and 60 h doubling time. STR DNA profiling revealed a unique genomic identity not matching any existing human cancer cell lines from the ATCC or DSMZ databases. Consistent with the mesenchymal origin, western blot was positive for vimentin and negative for the carcinoma marker cytokeratin. Within three‐dimensional (3D) culture, the cells formed spheroids of similar patterning and smaller size compared with MNNG‐HOS and U2OS cell lines. The chemotherapeutic drug sensitivity of OSA 1777 was evaluated in both 2D and 3D culture systems. In summary, we report OSA 1777 as a novel biological model of OSA amenable to future studies focused on OSA that recurs despite an initially strong chemotherapeutic response. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:902‐910, 2020

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Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Recurrent Osteosarcoma Cell Line: OSA 1777

Thanindratarn

Dean

et al. 2019

Journal Orthopaedic Research

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“…In response to cell stress, p53 is phosphorylated, preventing Mdm2 interaction and subsequent degradation [246]. In many tumors with WTp53, the p53 pathway is suppressed through amplification and overexpression of Mdm2 [247]. MDM2 SNP 309 is a T/G single nucleotide polymorphism in the promoter of MDM2 that increases affinity for the transcription factor Sp1, driving increased expression of Mdm2 mRNA and protein [248].…”

Section: Sex Differences In P53mentioning

confidence: 99%

Sex differences in cancer mechanisms

et al. 2020

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We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab-and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

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“…53 In many human cancers, loss of TP53 activity is due to the overexpression of the TP53-interacting protein MDM2. 54 The RING finger E3 ligase domain in MDM2 conjugates polyubiquitin chains onto TP53, targeting it for proteasomal degradation. 55 The MDM2 homolog MDMX (also known as MDM4) also inhibits TP53 activity.…”

Section: The Role Of Tp53 In Hscsmentioning

confidence: 99%

“…15 As previously addressed, a prominent route to the loss of TP53 activity is the overexpression of the TP53-interacting protein MDM2, found across human cancers. 54 Importantly, MDM2 overexpression has been reported in up to 50% of AML. 9,[118][119][120][121][122] The MDM2 protein regulates TP53 ubiquitination, and subsequently, its proteasomal degradation.…”

Section: Leveraging Wild-type Tp53 For Therapymentioning

confidence: 99%

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

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The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

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The Role of MDM2 Amplification and Overexpression in Tumorigenesis

Cited by 189 publications

References 79 publications

Establishment and Characterization of a Recurrent Osteosarcoma Cell Line: OSA 1777

Establishment and Characterization of a Recurrent Osteosarcoma Cell Line: OSA 1777

Sex differences in cancer mechanisms

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

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