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)

This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The expression of matrix metalloproteinase-2, -9 (MMP-2, MMP-9), tissue inhibitor-1 of matrix metalloproteinase (TIMP-1), cell adhesion molecule 44 variant 6 (CD44v6), HER2/neu and p53 was investigated in 154 patients with head and neck squamous cell carcinoma (SCC) by ABC and ImmunoMax immunohistochemical method. Their clinical relevance and correlation were analysed. The expression of MMP-2, MMP-9, TIMP-1, CD44v6, HER2/neu and p53 was found in cancer cells in 87.01%, 85.71%, 68.18%, 98.05%, 55.19% and 50.65% cases respectively. Linear regression and correlation analysis revealed that there was close positive relationship (P<0.05) between the expression of MMP-2 and MMP-9, TIMP-1 and CD44v6, HER2/neu and MMP-9, MMP-2 and p53. Up-regulation of MMP-2 was accompanied by advanced T stage (P<0.01). There was also a trend of MMP-2 expression being related with tumor metastasis. Increased expression of HER2/neu was found in patients with tumor recurrence(P<0.05). The expression of TIMP-1 was higher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non-keratinizing SCC than that in basaloid SCC(P<0.05). These findings suggested that MMP-2 and MMP-9, HER2/neu and MMP-9, MMP-2 and p53 had a coordinate function in aggression of tumor; that MMP-2 had a more important function than MMP-9 in tumor invasion and metastasis; and that HER2/neu might serve as a biomarker for poor prognosis in HNSCC.
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PMID:Correlation of matrix metalloproteinase-2, -9, tissue inhibitor-1 of matrix metalloproteinase and CD44 variant 6 in head and neck cancer metastasis. 1286 29

Malignant melanomas are frequently characterized by elevated levels of wild-type p53, suggesting that p53 function could be suppressed by a mechanism different from p53 mutation. We analysed the functionality of the p53-signaling pathway in a panel of seven human melanoma cell lines consisting of one p53-deficient line, two lines with mutant p53, and four lines expressing wild-type p53. Only lines with wild-type p53 were characterized by elevated levels of endogenous p21, high activity of p53-responsive reporters and accumulation of p53 in response to genotoxic stress, common properties of functional p53. The presence of wild-type p53 was associated with depletion or loss of p14ARF and p16 expression. The levels of p33ING1b and p24ING1c, two major products of Ing1 locus and putative coregulators of p53, were elevated in all cell lines tested; however, ectopic expression of either ING1 isoform had no effect on cell proliferation. All lines retained expression of Apaf-1, and all but one remained sensitive to ectopic expression of retrovirus-transduced p53. Our data indicate that regardless of abnormally high levels of p53 in melanomas, their p53 remains competent in transactivation of its targets, and, if highly overexpressed, capable of growth inhibition. Hence, the p53 pathway in malignant melanomas can be considered for pharmacological targeting and anticancer gene therapy.
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PMID:Melanoma cells can tolerate high levels of transcriptionally active endogenous p53 but are sensitive to retrovirus-transduced p53. 1289 34

The multistep process of tumorigenesis has not been decoded to date, although numerous investigations into probable molecular changes have meanwhile been conducted. However, not only DNA changes or loss of alleles cause deregulation of gene function, but also epigenetic alterations (e.g. methylation) result in functional loss. The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14ARF and p16INK4a, which play active roles in the p53 and Rb tumor suppressive pathways. We therefore examined not only p16 and p14 proteins, but also alterations of the INK4a-ARF locus, including methylation and loss of heterozygosity in benign and malignant tumors of the head and neck (squamous cell carcinomas and pleomorphic adenomas). In benign pleomorphic adenomas, methylation of p14ARF was found in 1 out of 42 (2%) cases, whereas alterations of p16INK4a occurred in 12/42 (29%) pleomorphic adenomas. In HNSCC, methylation of p16INK4a occurred in 16 out of 50 (32%) carcinomas. P14ARF was found to be methylated in 8 out of 50 cases (16%). Our results demonstrate that alterations of the INK4a-ARF locus are frequent and important events not only in the carcinogenesis of malignant, but also in benign tumors.
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PMID:Genetic and epigenetic alterations of 9p21 gene products in benign and malignant tumors of the head and neck. 1292 39

The ING family of proteins is involved in the regulation of diverse processes ranging from cell cycle and cellular senescence to apoptosis. These effects are most likely through activation of acetylation-dependent pathways that ultimately alter gene expression. Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 function has not been elucidated. In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. The p47(ING1a) isoform also repressed AFP promoter activity, but in contrast to other ING isoforms, it repressed the p21(WAF1) promoter. p47(ING3) up-regulated p21(WAF1) promoter activity, but it did not have any effect on the AFP promoter. ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. Indeed, electrophoretic mobility shift assays confirmed that HNF1 binds to AT-motifs, but we found, surprisingly, that the ING1 complexes binding to these AT-motifs were devoid of HNF1 protein. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. In addition, we found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382). These findings provide novel evidence that p33(ING1b) represses AFP transcription by at least two mechanisms, one of which includes p53. The first is by binding to the AT-motif and excluding HNF1 binding while possibly targeting HAT activity to promoter regions, and the second is by increasing the levels of active, acetylated p53 via binding and inhibiting the ability of hSIR2 to deacetylate p53 protein.
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PMID:ING1 represses transcription by direct DNA binding and through effects on p53. 1452

ING1b can stimulate cell cycle arrest, repair, senescence, and apoptosis. The actions of ING1b are attributed to its activation of the tumor suppressor p53. Here we investigate the more subtle effects of ING1b on the cell cycle and DNA damage responses in the absence of p53. To this end, we have generated isogenic cell lines that expressed ING1b and p53 either individually or in combination under the control of inducible promoters. A five- to 10-fold induction of ING1b over the endogenous protein in a p53-null H1299 background slightly impairs proliferation by increasing the doubling time by approximately 10%. Significantly, ectopic expression of ING1b enhanced the G(2)/M DNA damage checkpoint induced by adriamycin. We demonstrated that the DNA damage-induced cell death mediated by the cooperation between ING1b and p53 was more prominent than by the individual proteins alone. In adriamycin-treated cells, p53 was stabilized and induced the expression of p21(CIP1/WAF1), but the expression of ING1b was not affected. The exact targets of ING1b in the p53-null background are not known, but we demonstrated that the transcriptional activities of other members of the p53 family, p63alpha and p73alpha, could be activated by ING1b. These data indicate that ING1 has a subtle antiproliferative effect even in the absence of p53, and ING1b enhances the DNA damage responses through p53-dependent and -independent mechanisms.
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PMID:ING1b decreases cell proliferation through p53-dependent and -independent mechanisms. 1457 37

Molecular studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated multiple genetic abnormalities such as activation of various oncogenes (Ras, Myc, epidermal growth factor receptor, and cyclin D1), tumor suppressor gene inactivation (TP53 and p16), and loss of heterozygosity at numerous chromosomal locations. Despite these observations, accurate and reliable biomarkers that predict patients at highest risk for local recurrence have yet to be defined. In an effort to identify gene expression signatures that may serve as biomarkers, we studied 41 squamous cell carcinoma tumors (25 primary and 16 locally recurrent) from various anatomical sites and 13 normal oral mucosal biopsy samples from healthy volunteers with microarray analysis using Affymetrix U133A GeneChip arrays. Differentially expressed genes were identified by calculating generalized t tests (P < 0.001) and applying a series of filtering criteria to yield a highly discriminant list of 2890 genes. Hierarchical clustering and image generation using standard software were used to visualize gene expression signatures. Several gene expression signatures were readily identifiable in the HNSCC tumors, including signatures associated with proliferation, extracellular matrix production, cytokine/chemokine expression, and immune response. Of particular interest was the association of a gene expression signature enriched for genes involved in tumor invasion and metastasis with patients experiencing locally recurrent disease. Notably, these tumors also demonstrated a marked absence of an immune response signature suggesting that modulation of tumor-specific immune responses may play a role in local treatment failure. These data provide evidence for a new gene expression-based biomarker of local treatment failure in HNSCC.
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PMID:Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. 1472 8

Human papillomavirus type 16 (HPV16) is associated with squamous cell carcinomas of the head and neck (HNSCC) particularly from the Waldeyer's tonsillar ring. A causal role of HPV16 in carcinogenesis is linked to the activity of the viral oncoproteins E6 and E7 which inactivate the cellular tumor suppressors p53 and pRB, respectively. Lack of E6 expression in HPV16-positive HNSCC has been reported, in some cases caused by disruption of the E6 gene. We have examined the status of the HPV16 E6-E7 gene region in tumor and metastasis samples of 24 HNSCC patients employing genomic PCR. No cases with a disrupted E6-E7 region could be identified. Sequence analysis of the E6-E7 segments revealed three different HPV16 E6-E7 genotypes: the HPV16 prototype (6 of 21 cases), the E6 variant T350G (8 of 21 cases), and the E6-E7 variant A131G/C712A (7 of 21 cases). The E6 variants T350G and A131G have been associated with increased oncogenic potential in cervical cancer patients depending on host genetic factors. Their high prevalence in the HNSCC samples studied indicates that they may be important also in HNSCC development.
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PMID:Human papillomavirus type 16 E6 and E7 genotypes in head-and-neck carcinomas. 1500 25

Measurements of genomic instability, or identification of genes responsible for instability, may potentially be used as molecular markers to predict disease course and response to therapy. Other possible applications include use of genomic instability measurements, or genes, as tools to screen for primary or recurrent disease. Methodologies for detection of genetic mutations in saliva, blood, and sputum have already been described[61,62]. Brennan et al [63] have described a molecular technique for analyzing histopathologically negative margins and lymph nodes for the presence of p53 gene mutation. This study showed that a positive molecular margin significantly predicted disease recurrence. The recognition that HNSCC is a genetically heterogeneous disease represents a major step toward developing an understanding of its underlying genetic basis. To develop an insight into this genetically heterogeneous disease, investigators must not only focus their efforts on specific head and neck disease sites. Laser-capture microdissection represents a powerful tool for isolating very specific cell populations from tumors [64]. Leethanakul et al[65] performed laser-capture microdissection on oral cavity SCC to construct stage-specific cDNA libraries. Sequencing of 96 clones from each of the six libraries constructed suggested the existence of 132 novel genes, which may play a role in the pathogenesis of HNSCC. The current literature suggests that many individuals diagnosed withHNSCC are genetically predisposed to developing malignancy because of some inherent deficiency of their capacity to maintain their genome in the presence of environmental stressors. Head and neck cancers are highly heterogeneous tumors and exhibit a wide variety of forms of genomic instability. Thus, genomic instability may be viewed as a fundamental force driving head and neck tumorigenesis and evolution. Future study of the specific genetic mechanisms that underlie genomic instability in the HNSCCpatient population is needed. It is only through study of this fundamental force that drives the development of these tumors that clinicians may gain the insight required to develop new diagnostic and therapeutic modalities to benefit the HNSCC patient population as a whole.
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PMID:The role of genomic instability in the pathogenesis of squamous cell carcinoma of the head and neck. 1506 58

Head and neck cancer (HNSCC) is one of the most distressing human cancers, causing pain and affecting the basic survival functions of breathing and swallowing. Mortality rates have not changed despite recent advances in radiotherapy and surgical treatment. We have compared the expression of over 13,000 unique genes in 7 cases of matched HNSCC and normal oral mucosa. Of the 1,260 genes that showed statistically significant differences in expression between normal and tumor tissue at the mRNA level, the three top ranking of the top 5% were selected for further analysis by immunohistochemistry on paraffin sections, along with the tumor suppressor genes p16 and p53, in a total of 62 patients including 55 for whom >4-year clinical data was available. Using univariate and multivariate survival analysis, we identified SPARC/osteonectin as a powerful independent prognostic marker for short disease-free interval (DFI) (p < 0.002) and poor overall survival (OS) (p = 0.018) of HNSCC patients. In combination with other ECM proteins found in our analysis, PAI-1 and uPA, the association with DFI and OS became even more significant (p < 0.001). Our study represents the first instance of SPARC as an independent prognostic marker in HNSCC.
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PMID:Novel markers for poor prognosis in head and neck cancer. 1549 18

p63 and p73 share significant structural and functional homologies with the tumour suppressor p53. Unlike the p53 gene, both encode for several isoforms which vary in their NH2 and COOH termini with variable and, in part, opposed biological functions. The objective of the present study was to analyse the expression profiles of p53 family members in squamous cell carcinomas of the head and neck (HNSCC) and their alterations caused by exposure to the clinically active drug cisplatin. Using multiplex RT-PCR combined with the Southern technique, we determined transcription of p53 family members in 10 established HNSCC cell lines. In the majority of HNSCC, p53 and different p63/p73 isoforms were expressed with cell-line-specific patterns for composition and intensity of transcript expression. Exposure to cisplatin caused multiple alterations in the p63 and p73 profiles suggesting a complex regulation which may influence the sensitivity to chemotherapy.
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PMID:p53, p63 and p73 expression in squamous cell carcinomas of the head and neck and their response to cisplatin exposure. 1560 18


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