Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P73, a p53-homologue gene, has been studied for its possible role in head and neck squamous epithelium (HNSE) differentiation and carcinogenesis. P73 RNA and protein were analysed in 50 biopsies, including well- and moderately-differentiated carcinomas, and 21 matched normal adjacent tissues. P73 immunohistochemical analyses revealed intense p73 nuclear staining in basal and parabasal cells of normal squamous epithelium, in contrast with complete absence of staining in the more superficial cell layers. Moderately-differentiated carcinomas demonstrated homogeneous and diffuse staining in all tumour cells, while only basal cells were stained in well-differentiated carcinomas as in normal tissue. No correlation was observed between p73 and p53 protein expression. Immunostaining for p63, another p53-related protein previously described as being involved in HNSE morphogenesis and overexpressed in head and neck squamous cell carcinomas (HNSCC), was found to be similar to p73 labelling in carcinomas, but spread to the more differentiated layers in normal epithelium. Biallelic expression of p73 was found in tumours as well as in matched normal tissues. Comparison of p73 transcript levels between tumours and normal tissues showed decreased mRNA expression in 5/17 (30%) tumours independently of the differentiation status. Mutation and loss of heterozygosity analyses of the p73 gene revealed wild type status and no deletion. Our results strongly suggest that: (i) p73 is associated with homeostasis and control of differentiation of head and neck squamous epithelium probably in concert with p53 and p63; (ii) down-regulation of p73 expression could participate in HNSE carcinogenesis.
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PMID:P73 expression in basal layers of head and neck squamous epithelium: a role in differentiation and carcinogenesis in concert with p53 and p63? 1153 43

Soft tissue sarcomas frequently carry p53 mutations reducing chemotherapeutical response. Especially malignant fibrous histiocytoma (MFH) reveals a reduced ifosfamide (IF) chemosensitivity when compared to other sarcoma entities. This is the first study to analyze MFH cells for the effects of IF on the expression of the pathways P16-CDK4-Rb and P14ARF-MDM2-P73 regulating cell cycle. The aim was to identify candidate genes possibly involved in the anti-apoptotic response of p53-deficient MFH cells during chemotherapy. PCR, real-time RT-PCR and confocal laser scanning microscopy were applied on primary cultures of MFH cells containing defective p53 genes. The cultures were treated with different concentrations of IF. A non-treated MFH culture served as negative control. A threshold concentration of IF (100 microM) was determined sparing the majority of the cells (99%), whereas higher IF quantities caused complete apoptosis. Data collected over a period of 48 h showed that the MFH cells surviving 100 microM IF overexpressed the kinase gene CDK4 and oncogene MDM2 by a factor of 63. A similar strong increase was observed at the protein level for both proteins. In contrast, the other proteins analyzed were not detectable. Additionally, the MFH cells induced complex patterns of MDM2 mRNA splicing and an abnormal mRNA transcript carrying a novel MDM2 missense mutation. These effects were neither observed in the non-treated culture nor in cultures completely inducing spontaneous apoptosis. Therefore, we speculate that the induction of the gene CDK4, and especially of MDM2, is involved in anti-apoptotic mechanisms of p53-negative MFH cells tolerating IF in vitro. Further experiments are necessary to test whether the novel candidate genes favor development of chemoresistance and whether MDM2 mRNA splicing variants contribute to this process in vivo.
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PMID:Analysis of central regulatory pathways in p53-deficient primary cultures of malignant fibrous histiocytoma exposed to ifosfamide. 1573 17

The P73 gene is a homologue of the P53 tumor suppressor. Owing to its structural similarity with p53, p73 was originally considered to have tumor suppressor function. However, the discovery of N-terminal truncated isoforms with oncogenic properties showed a 'two in one' structure of its product, p73 protein. The full-length variants are strong inducers of apoptosis, whereas the truncated isoforms inhibit proapoptotic activity of p53 and the full-length p73. Thus, p73 is involved in the regulation of cell cycle, cell death and development. Moreover, it plays a role in carcinogenesis and controls tumor sensitivity to treatment. p73 is commonly expressed in tumor cells in hematological malignancies. Overexpression of p73 protein and aberrant expression of its particular isoforms, with very low frequency of P73 hypermethylation or mutations, were found in malignant myeloproliferations, including acute myeloblastic leukemia. In contrast, hypermethylation and subsequent inactivation of the P73 gene are the most common findings in malignant lymphoproliferative disorders, especially acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphomas. Assessment of P73 methylation may provide important prognostic information, as was confirmed in patients with ALL. This review summarizes some aspects of p73 biology with particular reference to its possible pathogenetic role and prognostic significance in hematological malignancies.
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PMID:The role of p73 in hematological malignancies. 1654 Nov 41

The P73 gene is transcribed from two promoters, P1 and P2, that direct the expression of multiple transactivation competent (TA) and dominant negative (DN) isoforms. TAp73 transcription factors mediate cell cycle arrest and/or apoptosis in response to DNA damage and are involved in developmental processes. P73 mRNA levels increase and the P1p73 promoter is upregulated during myogenic differentiation of C2C12 skeletal muscle satellite cells. The DNp73 proteins act as trans-repressors of p53- and p73-dependent transcription, and possess both antiapoptotic and pro-proliferative potential. Here, we show that DNp73alpha is expressed in proliferating C2C12 myoblasts, rapidly accumulates in differentiating myocytes and remains elevated in C2C12 myotubes. By combining transactivation assays and chromatin immunoprecipitation analysis, we could show that the upregulation of the P2p73 promoter during myogenic differentiation is mediated by the coordinated recruitment and activity of MyoD and p53/p73. Abrogation of DNp73 expression by specific siRNA led to a strong potentiation of the spontaneous apoptosis of C2C12 myoblasts induced to differentiate. Finally, unlike TAp73 that contributes to DNA damage-induced apoptosis of myotubes, endogenous DNp73 mediates the relative resistance of differentiated myotubes to DNA damage. Altogether, our findings identify DNp73alpha as an important target in designing strategies aimed at the potentiation of the regenerative potential of skeletal satellite cells.
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PMID:DNp73alpha protects myogenic cells from apoptosis. 1665 59

P73, a p53 homolog, has some p53-like activities and plays an important role in modulating cell cycle, apoptosis and DNA repair. The two linked polymorphisms in the non-coding region of exon2 of p73 gene, named G4C14-A4T14, may alter translation efficiency of the gene. The transcription of p73 gene is initiated by three promoters, termed P1-P3. There is a single nucleotide substitution (-386G/A) in the P3 promoter region with unknown function. To test the hypothesis that the genetic variations in the exon2 and P3 promoter play a role in the etiology of esophageal squamous cell carcinoma (ESCC), we conducted a population-based case-control study in 348 ESCC patients and 583 healthy controls from a high incidence region of Hebei province, China. The p73 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). The results showed that the family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC (the age, sex and smoking status adjusted OR = 2.02, 95% CI = 1.54-2.67). The overall distribution of the p73 genotype, allelotype and haplotype in cancer patients and controls were not significantly different (all P-values are above 0.05). Stratification analysis by smoking status and family history of UGIC also did not show the significant influence of the polymorphisms on the risk of ESCC development. The results suggested that the p73 exon2 G4C14-A4T14 and P3 promoter -386G/A polymorphisms might not be used as potential markers to predicate the risk of ESCC development in northern China.
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PMID:The p73 polymorphisms are not associated with susceptibility to esophageal squamous cell carcinoma in a high incidence region of China. 1761 76

P73 is located on chromosome 1p36, a region that is frequently deleted in neuroblastoma and other tumors. P73 has been postulated to be a candidate tumor suppressor and imprinted gene that shares significant homology with the p53 gene. To investigate the pattern of inactivation of this gene in human non-small cell lung cancers, we studied the six NSCLC cell lines to identify abnormal methylation in exon 1 and the allelic expression using StyI polymorphism analysis. We also examined the p73 gene expression in these six cell lines by reverse transcription-PCR as well as the expression of p73 protein in the five cell lines inducing tumors by immunohistochemistry. Homozygous allelic expression was demonstrated in all six cell lines and the GC/GC genotype was the predominant type. P73 was aberrantly methylated in all these six lung cancer cell lines. Complete loss of the p73 expression both at mRNA and the protein level was associated with the p73 methylation. Our results show that methylation of the p73 gene could be an important mechanism in silencing expression of this gene in human non-small cell lung cancers.
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PMID:Loss of p73 expression in six non-small cell lung cancer cell lines is associated with 5'CpG island methylation. 1802 56

Hedgehog-binding to Patched family receptors results in Smoothened-mediated activation of MAP3K10 (MST) and inactivation of SUFU. MAP3K10-induced DYRK2 phosphorylation combined with SUFU inhibition results in the stabilization and nuclear accumulation of GLI2 for transcriptional activation of GLI1, CCND1, CCND2, FOXA2, FOXC2, FOXP3, FOXQ1, RUNX2, and JAG2. Here, integrative genomic analyses on GLI2 orthologs were carried out. Rat Gli2 complete coding sequence was determined by assembling nucleotide sequences of exons 1, 2, and 5'-truncated rat Gli2 RefSeq (NM_001107169.1). GLI2 orthologs were more related to GLI3 orthologs than to GLI1 orthologs lacking the N-terminal repressor domain. betaTRCP1 (FBXW1)-binding DSYxxxS motif was conserved in GLI2 and GLI3 orthologs, while betaTRCP2 (FBXW11)-binding DSGxxxxxxxxxS motif in GLI2 and GLI1 orthologs. Human GLI2 mRNA was expressed in ES cells, NT2 cells, fetal lung, fetal heart, regenerating liver, gastric cancer, and other tumors. Mouse Gli2 mRNA was expressed in unfertilized egg, ES cells, and EG cells. Tandem RRRCWWGYYY motifs for P53, P63 or P73, and also four conserved bHLH-binding sites were identified within GLI2 proximal promoter region. Interaction map of P53 and stem cell signaling network were then constructed. P53-induced NOTCH1 upregulation leads to HES1, HES5, HEY1, HEY2 or HEYL upregulation for the repression of tissue specific bHLH transcriptional activators. DYRK2 functions as a positive regulator of P53-mediated apoptosis, and also as a negative regulator of the Hedgehog signaling cascade. GLI2 expression is regulated based on the balance of P53, Notch, and TGF-beta signaling, and Hedgehog signaling activation results in cell survival and proliferation due to transcriptional activation of Hedgehog-target genes, and also partly due to perturbation of P53-mediated transcriptional regulation.
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PMID:Integrative genomic analyses on GLI2: mechanism of Hedgehog priming through basal GLI2 expression, and interaction map of stem cell signaling network with P53. 1881 3

An important pathological aspect of Alzheimer's disease (AD) is the apoptosis of neuronal and glial cells. Two members of the same protein family that regulates many genes involved in apoptosis are P53 and the heterologue P73. One single nucleotide polymorphism (SNP) in the gene encoding P53 (Arg72Pro, RS1042522), one dinucleotide polymorphism (G4C14-to-A4T14, RS 2273953, RS1801173) in the gene encoding P73, and two further SNPs in the same gene (-386 G/A, RS3765728; exon 5 T/C, RS1801174) were studied to determine whether DNA variations could influence the occurrence of the disease in a sample of Italian subjects with the sporadic late-onset form of AD. We observed that carrying the Pro/Pro genotype of P53 Arg72Pro was a risk factor with respect to the Pro/Arg + Arg/Arg genotypes [Odds Ratio (OR) = 2.02; 95% Confidence Interval (CI) 1.02-4.00; p = 0.047]. Furthermore, carrying the G/G genotype of the P73 -386 G/A was a risk factor with respect to the G/A + A/A genotypes (OR = 4.27; 95% CI 1.00-18.65; p = 0.047). A significant result was also obtained for P73 G4C14-to-A4T14. Among the patients, the homozygotes for the AT allele of this SNP had developed AD symptoms 5 years earlier than other genotypes (ANOVA p = 0.017). Though the results of particular polymorphisms analyses were not highly significant after correction for multiple comparisons, present data suggest that variation at the two genes may have a role in AD occurrence.
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PMID:Association study between P53 and P73 gene polymorphisms and the sporadic late-onset form of Alzheimer's disease. 1965 86

We previously showed that AZD1152-HQPA, the inhibitor of Aurora B kinase potently induced growth arrest and apoptosis of various types of human leukemia cells including MV4-11 acute myelogenous leukemia (AML) cells, although the molecular mechanisms by which this class of kinase inhibitors induces apoptosis remain to be fully elucidated. We have recently established the MV4-11 subline, designated as MV4-11 TP53 R248W, which possesses transcriptionally inactive R248W mutation in the TP53 gene. MV4-11 TP53 R248W cells were relatively resistant to AZD1152-HQPA-mediated growth arrest, as measured by MTT and clonogenic assays. AZD1152-HQPA (10-100 nM, 48 h) strikingly induced apoptosis of MV4-11 cells, as assessed by Annexin V binding, loss of mitochondrial outer membrane potential, and activation of caspase cascade, in parallel with up-regulation of p53 and its target molecules Bax and Noxa. Notably, AZD1152-HQPA (10-100 nM, 48 h) induced polyploidy rather than apoptosis in MV4-11 TP53 R248W cells. The polyploid cells were eventually eliminated via apoptosis at later time period (72-120 h) in association with up-regulation of p73. Taken together, p53 plays an important role in AZD1152-HQPA-induced growth arrest and early onset of apoptosis in AML cells. P73 may mediate the late onset of apoptosis to eliminate the polyploid cells caused by the inhibitor of Aurora B kinase.
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PMID:p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells. 2001 23

P73 is a structural and functional homologue of p53, and plays an important role in regulating cell cycle and apoptosis. A potentially functional polymorphism (designated as p73 G4C14-to-A4T14) has been identified in a region in exon 2 of the p73 gene, which may theoretically form a stem-loop structure and thereby affect p73 expression. Several investigations have reported the correlation between p73 G4C14-to-A4T14 polymorphism and cancer risk. However, the results are inconclusive. To further assess the association between p73 polymorphism and cancer risk, we performed meta-analysis of the data sets obtained from 26 individual studies involving 8,148 cancer patients and 8,150 controls. The association between p73 G4C14-to-A4T14 polymorphism and cancer risk was determined by crude odd ratios (OR) with 95% CI (confidential interval). AT-allele carriers were found to have a significantly increased risk of cervical cancer (AT/GC vs. GC/GC, OR = 1.63, 95% CI = 1.14-2.33; AT/AT + AT/GC vs. GC/GC, OR = 1.49, 95% CI = 1.05-2.10), colorectal cancer (AT/AT vs. AT/GC + GC/GC, OR = 1.98, 95% CI = 1.25-3.12), head and neck cancer (AT/AT + AT/GC vs. GC/GC, OR = 1.44, 95% CI = 1.06-1.96) and other cancers (AT/AT vs. GC/GC, OR = 1.78, 95% CI = 1.24-2.57; AT/AT vs. AT/GC + GC/GC, OR = 1.80, 95% CI = 1.26-2.56). In the stratified analysis of ethnicity, a significantly elevated cancer risk was found in Caucasians (AT/AT + AT/GC vs. GC/GC, OR = 1.18, 95% CI = 1.08-1.30; allele AT vs. allele GC, OR = 1.15, 95% CI = 1.06-1.24). No significant association of p73 polymorphism with the cancer risk of smoking was detected by stratified analysis by smoking status. Together, our data suggest that the p73 G4C14-to-A4T14 may be a risk factor of cancer especially in Caucasians.
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PMID:Combined analysis of the association between p73 G4C14-to-A4T14 polymorphisms and cancer risk. 2161 40


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