p53 protein aggregation promotes platinum resistance in ovarian cancer

The tumor suppressor protein p53 is a transcription factor which plays a crucial role in maintaining genomic stability through the regulation of a vast repertoire of downstream target genes involved in cellular processes, such as cell cycle arrest, apoptosis, senescence, differentiation and DNA repair. Under normal cellular conditions, p53 is tightly regulated by its critical negative regulator MDM2, an E3 ligase which targets p53 for ubiquitin-mediated degradation. p14ARF is a tumor suppressor protein and the negative regulator of MDM2. Together, p53, MDM2 and p14ARF form an autoregulatory loop frequently inactivated in many human cancers. MDM2-p53 antagonists are small-molecule inhibitors designed to disrupt the interaction between p53 and MDM2 thereby nongenotoxically activating p53 in tumors with wild-type p53. Several MDM2-p53 antagonists are undergoing early clinical evaluation in adults and are anticipated to enter pediatric trials in the near future. In contrast to several other cancers, neuroblastoma is a predominantly p53 wild-type tumor; however, p53 pathway inactivation through MDM2 amplification and p14ARF aberrations have been reported. Nongenotoxic activation of wild-type p53 using MDM2-p53 antagonists alone and in combination with other agents offers a novel therapeutic strategy for patients with neuroblastoma to potentially improve survival and/or reduce the toxicity associated with current chemotherapy regimens.

p14arf

MDMX

10.1159/000382087

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Mdm2 and ARF

Cancer drug discovery and develogment/Cancer drug discovery and development (2002)

Andrea Klotzbücher Michael H.G. Kubbutat

p14arf

P53 protein

Negative regulator

10.1007/978-1-59259-153-4_10

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MYCN and the p53-MDM2/MDMX-p14ARF network in neuroblastoma amd response to MDM2-p53 antagonists

Laura D. Gamble

MDMX

p14arf

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Epigenetics in Carcinogenesis and Cancer Prevention

Annals of the New York Academy of Sciences (2003)

Peter A. Jones

Carcinogenesis is a stepwise process of accumulation of genetic and epigenetic abnormalities that can lead to cellular dysfunction. It has become clear that epigenetic changes are equally important for this multistep process to produce its results. This article describes the different roles that epigenetic modulation may play during carcinogenesis and how an early detection and chemopreventive intervention strategy that takes both sides of the equation into account would be advantageous.

Epigenesis

10.1111/j.1749-6632.2003.tb05976.x

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Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis

Nature Communications (2013)

Tongsen Zheng Jiabei Wang Yuhan Zhao Cen Zhang Meihua Lin

10.1038/ncomms3996

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Expression of p14ARF overcomes tumor resistance to p53.

PubMed (2002)

Wenge Lu Jiayuh Lin Jiandong Chen

Tumors without p53 mutation are often resistant to p53 gene therapy. We examined the mechanism using p53-resistant A549 cells and p53-sensitive H1299 cells. We found that p53 delivered by adenovirus is poorly expressed in A549 (ARF-null) cells but efficiently expressed in H1299 cells (ARF-positive). Strong p53 expression and apoptosis can be achieved in A549 cells using a p53 mutant resistant to degradation by MDM2 or by coexpression of ARF. The results suggest that enhanced MDM2 activity attributable to loss of ARF contributes to p53 resistance. Surprisingly, tumor cell lines with MDM2 gene amplification are still deficient for ARF expression, suggesting that MDM2 amplification does not substitute for ARF inactivation during tumor development.

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Null cell

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Decreased Mdm2 Expression Inhibits Tumor Development and Extends Survival Independent of Arf and Dependent on p53

PLoS ONE (2012)

Christine M. Eischen Kelli L. Boyd

Inactivation of the Arf-Mdm2-p53 tumor suppressor pathway is a necessary event for tumorigenesis. Arf controls Mdm2, which in turn regulates p53, but Arf and Mdm2 also have p53-independent functions that affect tumor development. Moreover, inhibition of oncogene-induced tumorigenesis relies on Arf and p53, but the requirements of Arf and p53 in tumor development initiated in the absence of overt oncogene overexpression and the role of Mdm2 in this process remain unclear. In a series of genetic experiments in mice with defined deficiencies in Arf, Mdm2 and/or p53, we show Mdm2 haploinsufficiency significantly delayed tumorigenesis in mice deficient in Arf and p53. Mdm2 heterozygosity significantly inhibited tumor development in the absence of Arf, and in contrast to Myc oncogene-driven cancer, this delay in tumorigenesis could not be rescued with the presence of one allele of Arf. Notably, Mdm2 haploinsufficieny blocked the accelerated tumor development in Arf deficient mice caused by p53 heterozygosity. However, tumorigenesis was not inhibited in Mdm2 heterozygous mice lacking both alleles of p53 regardless of Arf status. Surprisingly, loss of Arf accelerated tumor development in p53-null mice. Tumor spectrum was largely dictated by Arf and p53 status with Mdm2 haploinsufficiency only modestly altering the tumor type in some of the genotypes and not the number of primary tumors that arose. Therefore, the significant effects of Mdm2 haploinsufficiency on tumor latency were independent of Arf and required at least one allele of p53, and an Mdm2 deficiency had minor effects on the types of tumors that developed. These data also demonstrate that decreased levels of Mdm2 are protective in the presence of multiple genetic events in Arf and p53 genes that normally accelerate tumorigenesis.

Haploinsufficiency

Tumor progression

10.1371/journal.pone.0046148

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Citations (13)