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

We have identified a new human p53 homologue, p40 (p51/p63). This gene was mapped to the distal arm of 3q and was found to be essential for normal epithelial development. We used microsatellite and FISH analyses to search for genetic alterations of p40 in primary HNSCC. A more precise localization of p40 was completed using 6 known markers on 3q and a newly isolated microsatellite marker within the p40 gene. We also determined the genomic organization of the p40 gene using human YAC and BAC clones. Microsatellite analysis revealed that 14 of 26 (54%) primary HNSCC had allelic imbalance in at least 1 of the 7 microsatellite loci. However, FISH analysis with a p40 probe showed that a majority of HNSCC had an increased copy number of the locus regardless of allelic status. Thus, overrepresentation of the p40 locus may play an important role in the development of HNSCC.
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PMID:Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma. 1079 91

Patients with advanced stages of head and neck cancer frequently develop locoregional recurrence as well as distant metastases. These data indicate that traditional diagnostic methods such as histopathology and radiology are not sensitive enough to detect the small numbers of tumor cells which are left behind, defined as minimal residual disease (MRD). Sensitive diagnostic assays based on molecular markers appear to be powerful tools to improve the staging of these patients. At the DNA level, tumor-specific p53 mutations seem to have great potential for the detection of "occult" tumor cells at surgical margins and lymph nodes. At the RNA level HNSCC associated antigens like the E48 antigen, allow the detection of rare HNSCC cells in blood and bone marrow and, it is hoped, also in lymph nodes and lymph node aspirates. However, the molecular assays which are used to detect MRD are subject to certain (technical) problems which affect their sensitivity and specificity. In this paper we will present examples of molecular assays such as the plaque assay using p53 mutations and the E48 RT-PCR, and show their use for MRD detection in cervical lymph nodes. In addition, we will discuss the problems and pitfalls associated with these sensitive techniques.
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PMID:Molecular diagnosis of head and neck cancer. 1085 64

The candidate tumor suppressor ING1 was identified in a genetic screen aimed at isolation of human genes whose expression is suppressed in cancer cells. It may function as a negative growth regulator in the p53 signal transduction pathway. However, its molecular mechanism is not clear. The ING1 locus encodes alternative transcripts of p47(ING1a), p33(ING1b), and p24(ING1c). Here we report differential association of protein products of ING1 with the mSin3 transcriptional corepressor complex. p33(ING1b) associates with Sin3, SAP30, HDAC1, RbAp48, and other proteins, to form large protein complexes, whereas p24(ING1c) does not. The ING1 immune complexes are active in deacetylating core histones in vitro, and p33(ING1b) is functionally associated with HDAC1-mediated transcriptional repression in transfected cells. Our data provide basis for a p33(ING1b)-specific molecular mechanism for the function of the ING1 locus.
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PMID:Differential association of products of alternative transcripts of the candidate tumor suppressor ING1 with the mSin3/HDAC1 transcriptional corepressor complex. 1111 40

In 1953, Slaughter et al. [D. P. Slaughter et al., Cancer (Phila.), 6: 963-968, 1953] proposed the concept of field cancerization in patients with squamous cell carcinoma of the head and neck (HNSCC) and discussed its clinical significance for the development of second primary tumors and local recurrences. To define the process of field cancerization and its putative clinical implications, we analyzed genetic aberrations in HNSCC and the accompanying macroscopically normal mucosa. In 28 HNSCC patients, loss of heterozygosity was determined in tumor and five noncontiguous mucosal biopsies using eight microsatellite markers at 9p, 3p, and 17p. For patients who showed loss of heterozygosity in their mucosal biopsies, all margins of the surgical specimen were subsequently analyzed to determine the extension of the field. In these cases, additional markers at 8p, 13q, and 18q as well as p53 mutations were included to determine subclonal differences between field and tumor. Genetically altered fields were detected in 36% (10 of 28) of the HNSCC patients. The field varied in size between patients and consisted of genetically different subclones. In 7 of 10 cases, the field extended into the surgical margins. One particular patient with a genetically altered field in a surgical margin developed a local recurrence after 28 months of follow-up. Microsatellite analysis showed that this recurrence had more molecular markers in common with the nonresected premalignant field than with the original tumor, suggesting that this persistent field has progressed further into a new malignancy. Our data show that genetically altered mucosa remains after treatment in a significant proportion of HNSCC patients, which may explain in part the high frequency of local recurrences and second primary tumors. Adequate identification and risk assessment of these genetically altered fields may have profound implications for future patient management.
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PMID:Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. 1141 Apr 86

High-risk human papillomaviruses (HPVs) have been proposed to be associated with a subset of head and neck cancers (HNSCCs). However, clear biological evidence linking HPV-mediated oncogenesis to the development of HNSCC is hardly available. An important biological mechanism underlying HPV-mediated carcinogenesis is the inactivation of p53 by the HPV E6 oncoprotein. In the present study we investigated this biological relationship between HPV and HNSCC. In total 84 HNSCC tumors were analyzed for the presence of high-risk HPV nucleic acids by DNA polymerase chain reaction-enzyme immunoassay (PCR-EIA) and E6 reverse transcriptase (RT)-PCR as well as for the presence of mutations in the p53 gene. We found 20/84 HPV16 DNA-positive cases with one or more DNA assays, 10 of which were consistently positive with all assays. Only 9/20 cases showed E6 mRNA expression, indicative for viral activity. Only these nine E6 mRNA-positive cases all lacked a p53 mutation, whereas both the other HPV DNA-positive and HPV-DNA negative tumors showed p53 mutations in 36% and 63% of the cases, respectively. Moreover, only in lymph node metastases of HPV E6 mRNA-positive tumors both viral DNA and E6 mRNA were present. Our study provides strong biological evidence for a plausible etiological role of high-risk HPV in a subgroup of HNSCC. Analysis of E6 mRNA expression by RT-PCR or alternatively, semiquantitative analyses of the viral load, seem more reliable assays to assess HPV involvement in HNSCC than the very sensitive DNA PCR analyses used routinely.
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PMID:Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas. 1141 Aug 71

The INK4a gene locus on chromosome 9p21 encodes two proteins, p16(INK4a) and p14(ARF), which influence cell cycle control regulated by pRb and p53. The objective of this study was to use different methods for the analysis of the incidence of changes at the INK4a locus in head and neck cancer (HNSCC). Primary tumours were analysed for allelic imbalances (AI) with microsatellite markers for chromosome 9, by immunohistochemistry (IHC) and IHC with enhanced sensitivity by tyramide signal amplification (TSA-IHC), and by RT-PCR. No homozygous deletions at 9p21 were detected. AI at 9p21, which was found in approximately 60% of the tumours, completely failed to indicate the functional inactivation of the two INK4a gene products. Immunostaining of normal squamous epithelia revealed very low levels of p16(INK4a), whereas p14(ARF) was readily detectable. In 160 tumours, IHC suggested a loss of p16(INK4a) expression in 90%. However, by TSA-IHC, only 53.7% showed loss of p16(INK4a) expression, and this was consistent with the RT-PCR analyses. In 100 tumours analysed for both proteins, selective loss of p16(INK4a) occurred in 37%; loss of p14(ARF) was found in only 15%, and selective loss in only 4%; 11% of the tumours had lost both proteins. We conclude that only IHC with high sensitivity and the combined expression analysis of mRNAs and proteins is suitable for studying the role of INK4a in HNSCC. The INK4a gene expression defects are frequent but not universal and primarily affect p16(INK4a). Their clinical impact is still not clear.
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PMID:Detailed gene expression analysis but not microsatellite marker analysis of 9p21 reveals differential defects in the INK4a gene locus in the majority of head and neck cancers. 1143 63

The biological functions of the tumor suppressor ING1 have been studied extensively in the past 5 years since it was cloned. Of the three alternatively spliced forms of ING1, p24(ING1) has been the focus of much of past research. Information on the other currently known isoforms, p47(ING1), p32(ING1), and p27(ING1), has been lacking. ING1 shares many biological functions with p53. It has been reported to mediate growth arrest, senescence, apoptosis, anchorage-dependent growth, and chemosensitivity. Some of these functions, such as cell-cycle arrest and apoptosis, have been shown to be dependent on the activity of both ING1 and p53 proteins. In this review, we will examine what is known about ING1 up to this point and clarify the cloning errors originating from the isolation of this gene.
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PMID:The tumor suppressor ING1: structure and function. 1146 Nov 12

The p33ING1 protein is a regulator of cell cycle, senescence, and apoptosis. Three alternatively spliced transcripts of p33ING1 encode p47ING1a, p33ING1b, and p24ING1c. We cloned an additional ING family member, p33ING2/ING1L. Unlike p33ING1b, p33ING2 is induced by the DNA-damaging agents etoposide and neocarzinostatin. p33ING1b and p33ING2 negatively regulate cell growth and survival in a p53-dependent manner through induction of G(1)-phase cell-cycle arrest and apoptosis. p33ING2 strongly enhances the transcriptional-transactivation activity of p53. Furthermore, p33ING2 expression increases the acetylation of p53 at Lys-382. Taken together, p33ING2 is a DNA damage-inducible gene that negatively regulates cell proliferation through activation of p53 by enhancing its acetylation.
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PMID:DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53. 1148 24

Sin3 is an evolutionarily conserved corepressor that exists in different complexes with the histone deacetylases HDAC1 and HDAC2. Sin3-HDAC complexes are believed to deacetylate nucleosomes in the vicinity of Sin3-regulated promoters, resulting in a repressed chromatin structure. We have previously found that a human Sin3-HDAC complex includes HDAC1 and HDAC2, the histone-binding proteins RbAp46 and RbAp48, and two novel polypeptides SAP30 and SAP18. SAP30 is a specific component of Sin3 complexes since it is absent in other HDAC1/2-containing complexes such as NuRD. SAP30 mediates interactions with different polypeptides providing specificity to Sin3 complexes. We have identified p33ING1b, a negative growth regulator involved in the p53 pathway, as a SAP30-associated protein. Two distinct Sin3-p33ING1b-containing complexes were isolated, one of which associates with the subunits of the Brg1-based Swi/Snf chromatin remodeling complex. The N terminus of p33ING1b, which is divergent among a family of ING1 polypeptides, associates with the Sin3 complex through direct interaction with SAP30. The N-terminal domain of p33 is present in several uncharacterized human proteins. We show that overexpression of p33ING1b suppresses cell growth in a manner dependent on the intact Sin3-HDAC-interacting domain.
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PMID:Role of the Sin3-histone deacetylase complex in growth regulation by the candidate tumor suppressor p33(ING1). 1178 59

Tobacco and alcohol have been identified as the most important risk factors for squamous cell carcinomas of the head and neck (HNSCC). Especially for tobacco, some of the carcinogen-induced mutations that trigger transformation have been identified. Much attempt has been made to show a relationship between the mutations of growth regulatory genes, i.e. tumor suppressor- or oncogenes, and the exposure to specific exogeneous mutagens. One of the best examined genes - harboring the most DNA damages (DNA adducts) - caused by xenobiotics is p53. This tumor suppressor gene is an important regulator of cell cycle and apoptosis and is mutated in 40-60% of all HNSCC. Further studies link specific mutations of the ras oncogene to definite carcinogens. The question of why these mutations lead to cancer in some smokers but not in others, i.e. the individual's susceptibility to external carcinogens, remains unclear. One possibility is the individual's ability (or non-ability) of detoxifying carcinogenic xenobiotics or repairing the DNA damages they caused. There are several known polymorphisms of enzymes involved in detoxification as well as in DNA repair - which might explain the interindividual variable susceptibility to HNSCC in smokers and drinkers. However, the results of several examined polymorphisms are diverse or even controversial. The diversity might be due to ethnical differences, study populations, tumor localizations as well as intratumoral heterogeneity. In this review, we attempt to discuss the carcinogen-specific mutations as well as the genetic polymorphisms, which may transfer an enhanced susceptibility to suffer HNSCC.
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PMID:Carcinogen-induced site-specific mutagenesis and genetic susceptibility in squamous cell carcinoma of the head and neck. 1189 77


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