Association of HDM2 Transcript Levels with Age of Onset and Prognosis in Soft Tissue Sarcomas

Täubert, Helge; Bartel, Frank; Greither, Thomas; Bache, Matthias; Kappler, Matthias; Köhler, Thomas; Böhnke, Anja; Lautenschläger, Christine; Schmidt, Hannelore; Holzhausen, Hans-Jürgen; Hauptmann, Steffen; Würl, Peter

doi:10.1158/1541-7786.mcr-07-2150

Cited by 7 publications

(3 citation statements)

References 36 publications

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“…Another confirmatory study showed that the effect on patient survival of Mdm2/p53 cooverexpression was greater than the additive effects of each independently [67]. Additionally, high levels of Mdm2 mRNA expression are correlated with an earlier age of onset of soft-tissue sarcomas [60]. Altogether, these findings point to Mdm2 having p53-independent effects in the process of tumorigenesis.…”

Section: Mdm2 and Cancermentioning

confidence: 99%

p53-Independent Effects of Mdm2

Bohlman

Manfredi

2014

Subcellular Biochemistry

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Mdm2 is best known as the primary negative regulator of p53, but a growing body of evidence suggests that Mdm2 also has a number of functions independent of its role in regulating p53. Although these functions are not yet well-characterized, they have been implicated in regulating of a number of cellular processes, including cell-cycle control, apoptosis, differentiation, genome stability, and transcription, among others. It appears that Mdm2 exerts these functions through a surprisingly wide variety of mechanisms. For example, it has been shown that Mdm2 can ubiquitinate alternative targets, can stimulate the activity of transcription factors, and can directly bind to mRNA to regulate its stability. Dysregulation of p53-independent functions could be responsible for the oncogenic properties of Mdm2 seen even in the absence of p53, and may explain why approximately 10 % of human tumors overexpress Mdm2 instead of inactivating p53 through other mechanisms. As the p53-independent functions of Mdm2 present novel targets for potential therapeutic interventions, fully characterizing these cellular and pathogenic roles of Mdm2 will be important in the study of tumor biology and the treatment of cancer.

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Section: Mdm2 and Cancermentioning

confidence: 99%

p53-Independent Effects of Mdm2

Bohlman

Manfredi

2014

Subcellular Biochemistry

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“…High levels of alternative mdm2 splicing are seen in tissue samples from ovarian and bladder carcinomas, some types of leukemia, breast carcinoma, soft tissue sarcoma, Hodgkin’s lymphoma, glioblastoma, rhabdomyosarcomas, liposarcomas, and lung carcinomas. 5,9,10,13,47-51 Mouse model information suggests that the tumor promoting capacity of Mdm2 does not require inhibition of wild-type p53. Exogenous expression of Mdm2-FL in mice was documented in 1998 to predispose the animals to sarcomas in a p53-independent manner.…”

Section: Alternative Splicing Of Mdm2: Increasing Mdm2 Proteome Divermentioning

confidence: 99%

Splicing Up Mdm2 for Cancer Proteome Diversity

2012

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Cancer cells often have high expression of Mdm2. However, in many cancers mdm2 is alternatively spliced, with more than 40 mRNA variants identified. Many of the alternative spliced mdm2 mRNAs have the potential to encode truncated Mdm2 isoforms. These putative Mdm2 isoforms can theoretically increase the diversity of the cancer proteome. The 3 best characterized are Mdm2-A, Mdm2-B, and Mdm2-C. As described in this review, the exogenous expression of these isoforms results in paradoxical phenotypes of transformation-associated growth as well as the inhibition of growth. Interestingly, these Mdm2 isoforms contribute tumor-promoting capacity in p53-null backgrounds. Herein we describe how alternative splicing of mdm2 may result in Mdm2 protein products that alter signal transduction to promote tumorigenesis. The tumor promoting capacity of Mdm2 isoforms is discussed in the context of functions that do not require the inhibition of p53. When N-terminal portions of Mdm2 are missing, the biochemical functions encoded by exon 12 are proposed to become more important. This may result in growth promoting functions when wild-type p53 is absent or compromised. The p53-independent tumor promoting activity of Mdm2 is proposed to result from C-terminal biochemical contributions of DNA binding, RNA binding, nucleolar localization, and nucleotide binding.

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“…Isolation of total RNA and cDNA synthesis were performed according to standard protocols as described previously [19]. The cDNA was amplified by automated real-time quantitative TaqMan™ assays for the wild type LGR5/GPR49 and GPR49Δ5 transcript variants and Hypoxanthin- guanine -phosphoribosyltransferase (HPRT) transcript using kits from Roboscreen (AJRoboscreen GmbH, Leipzig, Germany).…”

Section: Methodsmentioning

confidence: 99%

A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients

et al. 2011

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BackgroundThe human leucine-rich, repeat-containing G protein-coupled receptor (LGR) 5, also called GPR49, is a marker of stem cells in adult intestinal epithelium, stomach and hair follicles. LGR5/GPR49 is overexpressed in tumors of the colon, ovary and liver and in basal cell carcinomas. Moreover, an expression in skeletal muscle tissues was also detected. However, there has been no investigation regarding the expression and function of LGR5/GPR49 in soft-tissue sarcomas (STS) yet.MethodsSeventy-seven frozen tumor samples from adult STS patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of wild type LGR5/GPR49 and a newly identified splice variant of LGR5/GPR49 lacking exon 5 (that we called GPR49Δ5) were quantified.ResultsA low mRNA expression level of GPR49Δ5, but not wild type LGR5/GPR49, was significantly correlated with a poor prognosis for the disease-associated survival of STS patients (RR = 2.6; P = 0.026; multivariate Cox's regression hazard analysis). Furthermore, a low mRNA expression level of GPR49Δ5 was associated with a shorter recurrence-free survival (P = 0.043). However, tumor onset in patients with a lower expression level of GPR49Δ5 mRNA occurred 7.5 years later (P = 0.04) than in patients with a higher tumor level of GPR49Δ5 mRNA.ConclusionAn attenuated mRNA level of the newly identified transcript variant GPR49Δ5 is a negative prognostic marker for disease-associated and recurrence-free survival in STS patients. Additionally, a lower GPR49Δ5 mRNA level is associated with a later age of tumor onset. A putative role of GPR49Δ5 expression in tumorigenesis and tumor progression of soft tissue sarcomas is suggested.

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Association of HDM2 Transcript Levels with Age of Onset and Prognosis in Soft Tissue Sarcomas

Cited by 7 publications

References 36 publications

p53-Independent Effects of Mdm2

p53-Independent Effects of Mdm2

Splicing Up Mdm2 for Cancer Proteome Diversity

A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients

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