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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonrandom interstitial deletions and monosomy of chromosomes 5, 7, and 17 in refractory myelodysplasia (MDS) and acute myelogenous leukemia (AML) suggest a multistep pathway that culminates in aggressive clinical course. Because cytogenetic studies frequently identify chromosome 5 and 17 deletions within a single clone, we searched for allele loss for 5q loci and TP53 gene mutations in the same leukemic samples. Cosegregating deletions of chromosomes 5 and 17 were found to specifically include the 5q13.3 interval between the loci D5S672 and D5S620/D5S626, a locus hypothesized to harbor a tumor suppressor gene(1) and the TP53 gene on 17p. A rare patient with secondary refractory MDS and an unbalanced translocation [der(5;17)], which resulted in deletions of the 5q13.3-qter and 17p loci, provided clues on the sequence of genetic alterations. Serial molecular analysis of this patient revealed a dysplastic clone with der(5;17), which gave rise to a leukemic clone on acquiring an inactivating mutation of TP53. Our findings are consistent with functional cooperation between a putative tumor suppressor gene at 5q13.3 that contributes toward the progression of early stages of MDS, and the TP53 gene when mutated, causes transformation to AML. (Blood. 2000;95:2138-2143)
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PMID:Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. 1070 86

A comparative genomic hybridization (CGH) approach provides identification of genomic gains and losses in a tumor specimen in a single experiment. Only 11 embryonal rhabdomyosarcomas (E-RMS) have previously been subjected to CGH. The underlying genetic events in this histologic subtype are not well defined. In this investigation, 12 E-RMS specimens from 10 patients entered into Intergroup Rhabdomyosarcoma Study (IRS) I-IV and two local patients were analyzed by CGH and fluorescence in situ hybridization (FISH). Gains of chromosomes or chromosomal regions 2 (50%), 7 (42%), 8 (67%), 11 (42%), 12 (58%), 13q21 (33%), and 20 (33%) and losses of 1p35-36.3 (42%), 6 (33%), 9q22 (33%), 14q21-32 (25%), and 17 (25%) were most prominent. Chromosomal regions 1p35-36.3 and 9q22 represent novel regions of loss. Importantly, loss of 9q22 corresponds to the locus of a putative tumor suppressor gene (PTCH), which has been shown to play a role in rhabdomyosarcoma in a mouse model of Gorlin syndrome. Loss of 1p36 corresponds to the locus for PAX7, a paired box containing gene characteristically altered in alveolar rhabdomyosarcoma. Moreover, loss of 1p36 is prominent in another common pediatric soft tissue tumor, neuroblastoma. Gains of 2, 7, 8, 12, and 13 and loss of 14 were seen in the sole prior E-RMS CGH series; thus, these data provide important confirmatory results. In contrast to this previous study, however loss, not gain, of chromosome 17 was observed in the current study. Chromosome 17 loss correlates well with previous descriptions of frequent allelic loss of 17p (TP53) in E-RMS. In summary, CGH and FISH analyses of 12 E-RMS specimens revealed novel genomic imbalances that may be useful in directing further molecular studies for the determination of E-RMS critically involved genes.
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PMID:Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: an intergroup rhabdomyosarcoma study. 1071 62

Deletions in the 5q14 region have been described in a variety of neoplasms, such as testicular germ cell tumors, ovarian, gastric and lung cancer. The high frequency of allelic losses observed in this region implies the presence of putative tumor suppressor gene(s) (TSGs). In the present study, we investigated in a series of 56 non-small cell lung carcinomas (NSCLCs) the allelic imbalance (Alm) within the 5q14 region, employing the D5S644 marker, and its relationship with p53 abnormalities, the kinetic parameters [proliferation index (PI) and apoptotic index (AI)] and the ploidy status of the carcinomas. AI at D5S644 was found at a frequency of 51.2%. The rather high percentage of Alm in stage I tumors suggests an early involvement in NSCLC development. LOH at 5q14 was associated with decreased AR in lung tumors insinuating the presence of a putative TSG(s) (P=0.008). Simultaneous alterations of both p53 and D5S644 locus were the most frequent pattern observed (37.5%). Cases demonstrating this profile also exhibited a marked decrease in AI (P=0.001). These findings imply a synergistic mechanism of co-operation between different TSGs. However, proliferation activity was dependent only on p53 status, leading to the assumption that the putative TSG(s) present at 5q14 may probably be involved in normal apoptotic procedures. Further studies are needed to identify the candidate gene(s).
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PMID:Allelic imbalance at the 5q14 locus is associated with decreased apoptotic rate in non-small cell lung carcinomas (NSCLCs). Possible synergistic effect with p53 gene alterations on apoptosis. 1081 90

The short arm of chromosome 1 is among the most frequently affected regions in various types of common adult cancers as well as in neuroblastoma. In a previous study of ours, frequent allelic imbalance at the TP73 locus at 1p36 was noted in lung cancer despite the absence of TP73 mutations. This suggested the possible existence of an as yet unidentified tumor suppressor gene on 1p. Our initial attempt using the candidate gene approach did not yield any somatic mutations in the 14-3-3sigma gene (official gene symbol, SFN), a mediator of G2 arrest by TP53. Detailed deletion mapping of the telomeric region of 1p was thus carried out as an initial step toward positional cloning. We used seven polymorphic markers in addition to TP73 to examine 61 primary lung cancers. Allelic imbalance at one or more loci of 1p36 was observed in 30 of the 61 cases, whereas D1S508 at 1p36.2 exhibited the highest frequency (45%) of allelic imbalance among the 1p36 markers examined. In contrast, two proximal markers at 1p32-34 showed significantly less frequent (11-14%) allelic imbalance. Consequently, the present study identified the shortest region of overlap between D1S507 and TP73, which included the most frequently affected marker, D1S508. In addition, several cases exhibited allelic imbalance confined to a subtelomeric region distal to D1S2845 at 1p36.3. The present findings warrant future studies to identify the putative tumor suppressor gene(s) at 1p36 to gain a better understanding of the molecular pathogenesis of lung cancer. Genes Chromosomes Cancer 28:342-346, 2000.
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PMID:Frequent allelic imbalance suggests involvement of a tumor suppressor gene at 1p36 in the pathogenesis of human lung cancers. 1086 41

p73, a structural homologue of the tumor suppressor gene, p53, has recently been identified and mapped to chromosome 1p36, where genomic loss of heterozygosity (LOH) often occurs in human hepatocellular carcinoma (HCC). To determine whether p73 is involved in the development of HCC and whether there is an inverse correlation between the mutations of p73 and p53, we examined 22 paired tumors/noncancerous liver tissues for allelic expression, LOH and mutation of p73 and for mutation of p53. p73 was biallelically expressed in noncancerous liver tissues and in 7 out of the 8 informative tumors. One tumor tissue expressed only a single allele. LOH of p73 was found in 2 out of the 11 (18%) informative cases. A tumor-specific five-nucleotide deletion mutation causing a reading frameshift/early truncation of p73 DNA-binding domain was found, in which case no concomitant mutation in the DNA-binding domain of p53 was identified. Nine out of the 22 cases (41%) contained tumor-specific mutations in the DNA-binding domain of p53. Two of the three cases with p73 genetic alternations had a tumor size of less than 2 centimeters. These results suggest that p73 is a biallelically expressed gene in the liver and that allelic loss and mutation of p73 is infrequent and may occur early in HCC. p73 is unlikely to be the putative tumor suppressor gene located at chromosome 1p36 in HCC.
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PMID:Genetic alternations of p73 are infrequent but may occur in early stage hepatocellular carcinoma. 1092 60

An allelic loss of the chromosome 1p36 region is frequently found in oligodendrogliomas, which suggests the presence of putative tumor suppressor gene(s) in the region. Since the p73 gene, which encodes a protein with significant homology with p53, is mapped to the 1p36.33 region, we examined genetic alterations of the p73 gene in oligodendrogliomas. We screened 10 specimens for mutation throughout the p73 coding regions by polymerase chain reaction (PCR)-single strand conformation polymorphism analysis and by sequencing aberrantly migrated PCR products. We found several polymorphic nucleotide changes, but no somatic mutations that caused an amino acid change. The p73 gene is thus unlikely to be a tumor suppressor gene for oligodendrogliomas.
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PMID:The p73 gene is not mutated in oligodendrogliomas which frequently have a deleted region at chromosome 1p36.3. 1095 17

Because of the absence of specific marker, the histological classification of gliomas remain controversial. Identifying the genetic alterations involved in gliomas makes it possible to define specific molecular pathway of tumoral progression and to define markers of prognostic and diagnostic relevance. For example, p53 mutations are frequent in low grade astrocytoma, anaplastic astrocytoma and secondary glioblastoma suggesting that it takes place at an early stage of development of astrocytic tumors, whereas inactivation of PTEN arises mainly in glioblastomas and EGFR amplification is preferentially associated with "de novo" glioblastoma. Loss of chromosomes 1p and 19q characterizes oligodendroglial tumors. However the putative tumor suppressor genes located on 1p and 19q and specifically inactivated are not known yet. Emerging technologies, like microarrays and microdissection, will allow to refine molecular data and provide a molecular classification of gliomas mechanism involved in the repair of the respiratory epithelium.
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PMID:[Genes implicated in glial tumors]. 1104 99

p14(ARF) is a putative tumor suppressor gene thought to modify the levels of p53. CpG sites within the 5'-flanking region and exon 1beta of p14(ARF) are targets of aberrant methylation and transcriptional silencing in human colorectal cancer (CRC). Here we have developed methylation-specific polymerase chain reaction (MSPCR) methods to detect methylation of CpG sites in p14(ARF) in CRC cell lines and primary CRC tumors, and correlated p14(ARF) mRNA expression with methylation in CRC cell lines using competitive quantitative reverse transcription-polymerase chain reaction methods. Ten CRC cell lines were studied; three (DLD-1, HCT15 and SW48) showed extensive methylation and six (Colo320, SW480, HT29, Caco2, SW837 and WiDr) were unmethylated; the other cell line, LoVo, showed partial methylation that affected exon 1beta but not the immediate upstream CpG sites. p14(ARF) mRNA was expressed at extremely low levels in fully methylated cell lines and at 10(4)- to 10(5)-fold higher levels in unmethylated cell lines. p14(ARF) expression in the partially methylated LoVo cell line was intermediate. Treatment of LoVo cells with 2 microM 5-aza-2'-deoxycytidine for 72 h was associated with marked (100-fold) induction of mRNA levels. Of 119 primary CRCs, 18% contained p14(ARF) methylation, although partial methylation was the most common pattern observed (in 67% of methylated tumors). Methylation of p14(ARF) was often accompanied by p16(INK4a) methylation; however, 50% of p14(ARF) methylated tumors contained unmethylated p16(INK4a). Methylation at p14(ARF) was associated with female gender, greater age, proximal anatomic location and poor differentiation, but not stage at diagnosis. A two-step MSPCR method for assaying p14(ARF) methylation in human tumors is described.
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PMID:Correlations of partial and extensive methylation at the p14(ARF) locus with reduced mRNA expression in colorectal cancer cell lines and clinicopathological features in primary tumors. 1106 68

Multiple enchondromatosis (Ollier's disease) is a nonhereditary disease characterized by multiple central (medullary) cartilaginous bone tumors of unknown pathogenesis. It usually involves the extremities with a unilateral predominance, and sarcomatous transformation may occur. We report an autopsy-based genetic study of a 34-year-old man presenting in early adolescence with multiple enchondromas of the extremities, predominantly left-sided, compatible with Ollier's disease. Twelve years after presentation, malignant transformation to a high grade chondrosarcoma occurred in a tibial enchondroma. The patient died after widespread metastatic disease. Loss of heterozygosity (LOH), in the tibial chondrosarcoma and its metastases, was identified exclusively on chromosome bands 13q14 and 9p21, while being absent in the femoral enchondroma analyzed. Similarly, p53 overexpression was identified immunohistochemically in the tibial chondrosarcoma and its metastases, while being absent in the femoral enchondroma; LOH at 17p13 however, was not demonstrable. It is hypothesized that inactivation of putative tumor suppressor genes at 9p21 and 13q14, and overexpression of p53, identified in the chondrosarcoma and its metastases, but absent in enchondroma, may be related to sarcomatous transformation in Ollier's disease.
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PMID:Malignant progression in multiple enchondromatosis (Ollier's disease): an autopsy-based molecular genetic study. 1107 Jan 22

Squamous cell carcinomas of the lung and cervix arise by neoplastic transformation of their respective tissue epithelia. In the case of cervical carcinomas, an increasing body of evidence implicates the human papillomavirus, HPV (types 16 and 18), as playing a pivotal role in this malignant transformation process. The HPV early genes E6 and E7 are known to inactivate the tumor suppressors p53 and Rb, respectively; this leads to disruption of cell cycle regulation, predisposing cells to a cancerous phenotype. However, the role of caveolin-1 (a putative tumor suppressor) in this process remains unknown. Here, we show that caveolin-1 protein expression is consistently reduced in a panel of lung and cervical cancer derived cell lines and that this reduction is not due to hyperactivation of p42/44 MAP kinase (a known negative regulator of caveolin-1 transcription). Instead, we provide evidence that this down-regulation event is due to expression of the HPV E6 viral oncoprotein, as stable expression of E6 in NIH 3T3 cells is sufficient to dramatically reduce caveolin-1 protein levels. Furthermore, we demonstrate that p53-a tumor suppressor inactivated by E6-is a positive regulator of caveolin-1 gene transcription and protein expression. SiHa cells are derived from a human cervical squamous carcinoma, harbor a fully integrated copy of the HPV 16 genome (including E6), and show dramatically reduced levels of caveolin-1 expression. We show here that adenoviral-mediated gene transfer of the caveolin-1 cDNA to SiHa cells restores caveolin-1 protein expression and abrogates their anchorage-independent growth in soft agar. Taken together, our results suggest that the HPV oncoprotein E6 down-regulates caveolin-1 via inactivation of p53 and that replacement of caveolin-1 expression can partially revert HPV-mediated cell transformation.
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PMID:Caveolin-1 expression is down-regulated in cells transformed by the human papilloma virus in a p53-dependent manner. Replacement of caveolin-1 expression suppresses HPV-mediated cell transformation. 1107 33


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