Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the possibility that a proportion of children with sporadic rhabdomyosarcoma (RMS) carry constitutional mutations of the p53 tumor suppressor gene. 33 patients with sporadic RMS at two large outpatient pediatric oncology clinics submitted blood samples. Genomic DNA was extracted from peripheral blood leukocytes and PCR was used to amplify exons 2-11 of the p53 gene. Amplified genomic DNA was screened for the presence of germline p53 mutations using single-strand conformation polymorphism (SSCP) analysis. The DNA sequence of those samples that showed aberrant migration of bands on SSCP analysis was determined to identify the precise nature of the gene mutations. Patient records were reviewed to assess clinical correlates of the mutant p53 carrier state. Heterozygous constitutional mutations were detected in 3/33 patient samples screened. Two of these missense mutations are located in exon 7 and one in exon 8 of the p53 gene. The presence of mutations was not correlated with tumor histology, stage, or site. However, an association between young age at diagnosis and presence of a constitutional p53 mutation was noted: 3/13 children under the age of 3 yr at diagnosis carried mutations, whereas none of 20 children over 3 yr of age at diagnosis harbored a detectable constitutional mutation. These results in children with RMS corroborates previous findings in other clinical settings suggesting that the mutant p53 carrier state may predispose individuals to malignancy at an early age. Although this study did not assess whether the mutations were preexisting or new germline alterations, assessment of close relatives of RMS patients for cancer risk and predictive genetic testing may be indicated.
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PMID:Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. 770 67

Previous studies have shown that human rhabdomyosarcoma cells are induced to differentiate by TPA, in the absence of appreciable alterations of the muscle regulatory genes and their products (1). The question was addressed whether the tumor suppressor p53 could be a target of TPA action in these cells. Genomic analysis by a Polymerase Chain Reaction/Single-Strand Conformation Polymorphism (PCR/SSCP) and direct sequencing indicate the presence of a mutation in exon VII at codon 248 (C to T transition) and a loss of heterozygosity of p53 gene in human rhabdomyosarcoma cell line (RD). It is here shown that transcription of p53 mRNA strongly decreases in RD cells induced to growth arrest and differentiate by TPA treatment. In these cells immunoprecipitation and immunoblot analysis show that both synthesis and total cellular concentration of the protein are also reduced by TPA. Nevertheless nuclear p53 accumulation is at much higher extent, whereas 32P-orthophosphate labelling, followed by immunoprecipitation, demonstrates a decrease of phosphorylation of both cytoplasmic and nuclear p53. These results indicate that TPA causes a number of alterations of mutant p53, likely mediated through a protein kinase C dependent mechanism, which might impair the transforming ability of mutant p53 in growth-arrested and differentiating RD cells.
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PMID:TPA-induced differentiation of human rhabdomyosarcoma cells involves dephosphorylation and nuclear accumulation of mutant P53. 803 10

The developmentally regulated human insulin-like growth factor II (IGFII) gene is expressed at high levels in many types of tumors and promotes the proliferation of tumor cells with a high incidence of p53 gene defects. We have previously shown that p53 inhibits IGFII P3 promoter activity and decreases endogenous IGFII gene expression derived from the P3 promoter in rhabdomyosarcomas by interfering with TBP binding to the TATA element of the IGFII P3 promoter. In this report, we demonstrate that wild-type p53 expression in rhabdomyosarcoma cell lines containing mutant p53 leads to a decrease in the activity of another active IGFII promoter, P4, and a 5-fold reduction of IGFII mRNA derived from the P4 promoter. This inhibition of P4 activity is associated with direct binding of p53 to the P4 proximal promoter element despite the lack of a p53 consensus binding site. Our results suggest that p53 inhibits IGFII P4 promoter activity by a mechanism different than its effect on the P3 promoter. These data also supply further evidence of cross-talk between the IGF and p53 signaling pathways.
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PMID:p53 regulates human insulin-like growth factor II gene expression through active P4 promoter in rhabdomyosarcoma cells. 950 29

We describe two Li-Fraumeni syndrome families. Family A was remarkable for two early childhood cases of adrenocortical tumours, family B for a high incidence of many characteristic cancers, including a childhood case of choroid plexus tumour. Using direct sequencing, we analysed exons 5-9 of the p53 gene in constitutional DNA of individuals from both families and found two novel germline mutations in exon 5. In family A, we detected a point substitution in codon 138 (GCC to CCC), which resulted in the replacement of the alanine by a proline residue. Family B harboured a single-base pair deletion in codon 178 (CAC to -AC), resulting in a frameshift and premature chain termination. Three out of six tumours examined from both families, a renal cell carcinoma, a rhabdomyosarcoma and a breast cancer, showed loss of heterozygosity and contained only the mutant p53 allele. The remaining three neoplasms, both adrenocortical tumours and the choroid plexus tumour retained heterozygosity. Immunohistochemistry with anti-p53 antibody confirmed accumulation of p53 protein in tumours with loss of heterozygosity, while the remaining tumours were p53 negative. These results support the view that complete loss of activity of the wild-type p53 need not be the initial event in the formation of all tumours in Li-Fraumeni individuals.
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PMID:Two Li-Fraumeni syndrome families with novel germline p53 mutations: loss of the wild-type p53 allele in only 50% of tumours. 956 35

The mammalian target of rapamycin (mTOR) has been shown to link growth factor signaling and posttranscriptional control of translation of proteins that are frequently involved in cell cycle progression. However, the role of this pathway in cell survival has not been demonstrated. Here, we report that rapamycin, a specific inhibitor of mTOR kinase, induces G1 cell cycle arrest and apoptosis in two rhabdomyosarcoma cell lines (Rh1 and Rh30) under conditions of autocrine cell growth. To examine the kinetics of rapamycin action, we next determined the rapamycin sensitivity of rhabdomyosarcoma cells exposed briefly (1 h) or continuously (6 days). Results demonstrate that Rh1 and Rh30 cells were equally sensitive to rapamycin-induced growth arrest and apoptosis under either condition. Apoptosis was detected between 24 and 144 h of exposure to rapamycin. Both cell lines have mutant p53; hence, rapamycin-induced apoptosis appears to be a p53-independent process. To determine whether induction of apoptosis by rapamycin was specifically due to inhibition of mTOR signaling, we engineered Rh1 and Rh30 clones to stably express a mutant form of mTOR that was resistant to rapamycin (Ser2035-->Ile; designated mTOR-rr). Rh1 and Rh30 mTOR-rr clones were highly resistant (>3000-fold) to both growth inhibition and apoptosis induced by rapamycin. These results are the first to indicate that rapamycin-induced apoptosis is mediated by inhibition of mTOR. Exogenous insulin-like growth factor (IGF)-I protected both Rh1 and Rh30 from apoptosis, without reactivating ribosomal p70 S6 kinase (p70S6K) downstream of mTOR. However, in rapamycin-treated cultures, the response to IGF-I differed between the cell lines: Rh1 cells proliferated normally, whereas Rh30 cells remained arrested in G1 phase but viable. Rapamycin is known to inhibit synthesis of specific proteins but did not inhibit synthesis or alter the levels of mTOR. To examine the rate at which the mTOR pathway recovered, the ability of IGF-I to stimulate p70S6K activity was followed in cells treated for 1 h with rapamycin and then allowed to recover in medium containing > or =100-fold excess of FK506 (to prevent rapamycin from rebinding to its cytosolic receptor FKBP-12). Our results indicate that, in Rh1 cells, rapamycin dissociates relatively slowly from FKBP-12, with a t1/2 of approximately 17.5 h. in the presence of FK506, whereas there was no recovery of p70S6K activity in the absence of this competitor. This was of interest because rapamycin was relatively unstable under conditions of cell culture having a biological t1/2 of approximately 9.9 h. These results help to explain why cells are sensitive following short exposures to rapamycin and may be useful in guiding the use of rapamycin analogues that are entering clinical trials as novel antitumor agents.
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PMID:Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. 1002 80

Repeated doses of beta-radiation in the mouse skin model have been reported to produce carcinomas and sarcomas with equal frequency. Among sarcomas, fibrosarcomas and osteosarcomas have been the predominant reported histologies. In this report we describe the beta-radiation induction of rhabdomyosarcoma (RMS), a histology previously undescribed with tumor induction protocols using ionizing radiation in an animal model. Radiation-induced RMS is often seen as a secondary tumor following therapeutic irradiation for retinoblastoma in children. In our experiment the backs of 50 CD-1 mice were irradiated 3 times weekly for 35 weeks using a 90Sr source. The initial dose was 5.5 Gy/application, which was later reduced to 3 Gy after 15 weeks due to severe skin reactions. In all, 27 skin and subcutaneous tumors were seen and collected. Of 12 sarcomas seen, 9 had a rhabdoid histology; cell lines from 3 such tumors as well as a squamous-cell carcinoma (SCC) and a malignant fibrous histiocytoma (MFH) were established. Immunohistochemical analysis of their parent tumors showed that the rhabdoid tumors expressed desmin, which established the diagnosis of RMS. Two-dimensional gel electrophoresis and Western analysis of insoluble protein extracts confirmed that the cell lines from RMS tumors expressed desmin. A screen for molecular alterations identified a mutant p53 phenotype for RMS and MFH cell lines. These radiation-induced RMS cell lines provide a unique opportunity to study the molecular biology of this tumor in an animal model and will help provide insight into the mechanisms of radiation-induced RMS in humans.
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PMID:Experimental induction of rhabdomyosarcoma in mice with fractionated doses of beta-irradiation. 1035 30

The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in transformation. The expression of the IGF-IR gene is negatively regulated by a number of transcription factors, including the WT1 and p53 tumor suppressors. Previous studies have suggested both physical and functional interactions between the WT1 and p53 proteins. The potential functional interactions between WT1 and p53 in control of IGF-IR promoter activity were addressed by transient coexpression of vectors encoding different isoforms of WT1, together with IGF-IR promoter-luciferase reporter constructs, in p53-null osteosarcoma-derived Saos-2 cells, wild-type p53-expressing kidney tumor-derived G401 cells, and mutant p53-expressing, rhabdomyosarcoma-derived RD cells. Similar studies were also performed to compare p53-expressing Balb/c-3T3 and clonally derived p53-null, (10)1 fibroblasts and the colorectal cancer cell line HCT116 +/+, which expresses a wild-type p53 gene, and its HCT116 -/- derivative, in which the p53 gene has been disrupted by homologous recombination. WT1 splice variants lacking a KTS insert between zinc fingers 3 and 4 suppressed IGF-IR promoter activity in the absence of p53 or in the presence of wild-type p53. WT1 variants that contain the KTS insert are impaired in their ability to bind to the IGF-IR promoter and are unable to suppress IGF-IR promoter. In the presence of mutant p53, WT1 cannot repress the IGF-IR promoter. Coimmunoprecipitation experiments showed that p53 and WT1 physically interact, whereas electrophoretic mobility shift assay studies revealed that p53 modulates the ability of WT1 to bind to the IGF-IR promoter. In summary, the transcriptional activity of WT1 proteins and their ability to function as tumor suppressors or oncogenes depends on the cellular status of p53.
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PMID:WT1-p53 interactions in insulin-like growth factor-I receptor gene regulation. 1244 79

MDM2 is an oncoprotein best characterized for its role in the inactivation and degradation of the p53 tumor suppressor. However, MDM2 has many other binding partners and its p53-independent role in the regulation of cell growth and survival appears to be extremely complex. This report describes the expression of MDM2 in two rhabdomyosarcoma cell lines, both expressing a mutant p53 gene. Expression of MDM2 in Rh30 cells enhanced cell growth whereas expression of MDM2 in RD cells suppressed their growth and enhanced the rate of spontaneous apoptosis. The mechanism for these opposite phenotypes was demonstrated to be due to differential effects on the NFkappaB pathway. Previously MDM2 has been shown to activate NFkappaB through activation of transcription of the p65RelA subunit. In Rh30 cells MDM2 acted similarly to previously described, thereby promoting growth of Rh30 cells. In untreated RD cells p65RelA was constitutively overexpressed resulting in activation of the NFkappaB pathway. Expression of MDM2 in RD cells transcriptionally repressed p65RelA and suppressed NFkappaB activity, resulting in a reduced growth rate and enhanced apoptosis. The MDM2-sensitive region of the p65 promoter was localized to a 225 bp fragment to which MDM2 protein was shown to bind. The observation that MDM2 induces apoptosis under certain circumstances may help to explain the apparently surprising clinical studies that have shown that MDM2 expression in tumors is often associated with a favorable prognosis.
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PMID:MDM2 displays differential activities dependent upon the activation status of NFkappaB. 1793 75

Pleomorphic rhabdomyosarcoma is the most common variant of this tumour in adults and has a very poor outcome. Two genes which are known to play a role in rhabdomyosarcoma development are KRas and p53. In the majority of human tumours, p53 abnormalities are point mutations that result in the expression of a mutant form of the protein. It is now hypothesized that these mutant forms of p53 may be playing an oncogenic role, over and above simple loss of the wild-type function. In this study, we use Cre-LoxP technology to develop a novel mouse model of rhabdomyosarcoma, crossing mice expressing a common KRas mutation (G12V) with mice that either lose p53 expression or express a mutant form of p53. We use this model to explore the different effects of p53 loss and mutation in the setting of an activating KRas mutation. We found that either complete loss of p53 (p53(fl/fl)) or the expression of one mutant p53 allele with concomitant loss of the second allele (p53(R172H/+)) resulted in the rapid development of rhabdomyosarcoma in 15/16 and 19/19 mice, respectively. In contrast, there was a marked difference between mice which lose a single copy of p53 (p53(fl/+)) and mice expressing a single copy of mutant p53 (p53(172H/+)). Fourteen out of 16 p53(R172H/) mice developed rhabdomyosarcoma, compared with two out of 31 p53(fl/+) mice. As a consequence of this, p53(fl/+) mice had a median lifespan nearly double that of the p53(R172H/+) mice. To underline the enhanced effect of p53 mutation in tumour progression, metastases were seen only in those mice which expressed the mutant form. These data demonstrate that mutant p53 can co-operate with activated, mutant KRas to influence tumourigenesis and metastatic potential, over and above simple loss of normal protein function.
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PMID:p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. 2082 51

Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma of childhood in need of more effective therapeutic options. The expression of p53 in RMS is heterogeneous such that some tumors are wild-type whereas others are p53 mutant. The small molecule CP-31398 modulates both the wild-type and the mutant p53 proteins. Here, we show that CP-31398 blocks the growth of RMS cells that have either wild-type or mutant p53 status. In wild-type A204 cells, CP-31398 increased the expression of p53 and its downstream transcriptional targets, p21 and mdm2; enhanced the expression of apoptosis-related proteins; and reduced proliferation biomarkers. Flow profiling of CP-31398-treated cells indicated an enhancement in sub-G(0) and G(1) populations. CP-31398 inhibited proliferation in a manner associated with co-induction of SOX9 and p21. Apoptosis induced by CP-31398 occurred with translocation of p53 to mitochondria, leading to altered mitochondrial membrane potential, cytochrome c release, and reactive oxygen species release. In vivo, CP-31398 decreased the growth of tumor xenografts composed of wild-type or mutant p53 tumor cells, increasing tumor-free host survival. Our findings indicate that the ability of CP-31398 to modulate wild-type and mutant p53 results in the inhibition of RMS growth and invasiveness.
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PMID:Targeting wild-type and mutant p53 with small molecule CP-31398 blocks the growth of rhabdomyosarcoma by inducing reactive oxygen species-dependent apoptosis. 2068


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