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)

Twenty-five cases of thyroid adenomas with Hurthle cell changes, both pure and focal, were studied histologically and immunohistochemically with two objectives: first to elucidate the relationship between the normal uninvolved thyroid and the adenoma; and second, to evaluate the role of immunohistochemical studies in adenomas with Hurthle cell changes. Representative sections were stained with a panel of nine antibodies directed against thyroglobulin (TG), high molecular weight keratin (HMK), low molecular weight keratin (LMK), p53, bcl-2, epithelial membrane antigen (EMA), S100, carcinoembryonic antigen (CEA) and HMB45. In all cases, uniform strong positive staining (+3) with TG and bcl-2 was seen in the normal thyroid tissue while the adenoma stained moderately positive (+2). The reverse pattern was observed with LMK staining. Non-adenomatous thyroid cells were p53-negative, the majority of the Hurthle cells, however, were p53-positive and adenomas with an increased number of Hurthle cells had an increased percentage of p53 staining. The expression of EMA was variable. All thyroid cells both outside and within the adenoma were S100-, CEA-4 and HMB45-negative in all cases. The exact significance of p53 overexpression in the Hurthle cells needs further evaluation.
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PMID:Immunohistochemical analysis of thyroid adenomas with Hurthle cells. 953 99

Oncocytic neoplasms of the adrenal gland are rare. We describe the clinicopathologic and immunohistochemical findings of seven oncocytic adrenocortical neoplasms, five oncocytomas, and two oncocytic neoplasms of uncertain malignant potential. Three tumors were studied using electron microscopy. These neoplasms occurred in five women and two men (median age, 55 years) with no clinical evidence that the neoplasms were functional. The size of the neoplasms varied from 5.0 cm to 13.5 cm. Histologically, each neoplasm was composed exclusively of oncocytes. The oncocytomas had very low or absent mitotic activity and no evidence of necrosis. The two oncocytic neoplasms of uncertain malignant potential had increased mitotic activity and necrosis but no evidence of invasion or metastases. Nuclear atypia, either focal or generalized, was found in all neoplasms. Immunohistochemical studies performed using fixed, paraffin-embedded sections showed strong reactivity with the mitochondrial antibody mES-13 in all neoplasms. Four of five oncocytomas and one oncocytic neoplasm of uncertain malignant potential expressed keratin, predominantly keratin 18, as shown using the CAM 5.2 and AE3 antibodies. Two neuroendocrine-associated markers, neuron specific enolase and synaptophysin, were positive in seven and five neoplasms, respectively. However, all neoplasms were negative for the other neuroendocrine markers tested, including chromogranin A, tyrosine hydroxylase, and dopamine beta-hydroxylase, as well as for epithelial membrane antigen, S100, and p53. Using the MIB-1 (Ki-67) antibody, proliferative activity was increased in both oncocytic neoplasms of uncertain malignant potential. All six patients with available clinical follow-up data are alive without evidence disease, although the follow-up interval is relatively short (< 2 years) for the two patients with oncocytic neoplasms of uncertain malignant potential. We conclude that oncocytic adrenocortical neoplasms are nonfunctional tumors that can become large before they are detected by radiologic studies. The majority of neoplasms are benign and should not be misdiagnosed as carcinoma.
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PMID:Oncocytic adrenocortical neoplasms: a report of seven cases and review of the literature. 959 31

Skin cancer is one of the most prevalent forms of human neoplasia with a frequency approaching that of all other neoplasms combined. Given this alarming statistic, which may be further exacerbated by increased ultraviolet B irradiation from ozone depletion, it is vital that realistic, relevant model systems are developed to increase our understanding of the underlying molecular mechanisms of carcinogenesis that result in or evaluate new treatment modalities. Toward this goal, the ability to stably introduce genes into the germline of mice has greatly enhanced prospects for generation of transgenic animal models of multistage molecular carcinogenesis. Moreover, when genes are combined with regulatory sequences that target their expression to specific tissues, investigators are able to study neoplasia both in the context of living organisms and in the tissues suspected of being the targets of these genes. The epidermis is an attractive tissue for targeted gene expression; not only is it a model for epithelial diseases in general, but the accessibility of the epidermis allows easy detection of progressive pathological changes that result from transgene expression and facilitates assessment of the potential role played by environmental factors. We have developed a targeting vector based on the human keratin gene (HK1), which is expressed exclusively in the epidermis of transgenic mice, at a late stage in development and in both basal and differentiated cells. Through the use of this targeting ability, rasHa, fos, and TGF alpha transgenic mice have been developed that exhibit preneoplastic epidermal hyperplasia and hyperkeratosis, and later benign, regression prone papillomas. Together, coexpression of two oncogenes cooperated to give autonomous papillomas, which possessed the phenotypic stability to allow assessment of a third genetic event, namely loss of the p53 tumor suppressor gene, via mating with p53 knockout mice. Loss of p53 expression, however, identified a paradoxical block of papillomatogenesis. This latter result suggests that the epidermis possesses several mechanisms that can effectively compensate for the loss of important tumor suppressor functions and may have evolved to render the skin relatively resistant to the effects of environmental carcinogens.
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PMID:Multistage epidermal carcinogenesis in transgenic mice: cooperativity and paradox. 962 12

Polycyclic aromatic hydrocarbons (PAH) are a class of chemical carcinogens whose active metabolites form DNA adducts, resulting in specific mutational events. The tumor suppressor protein p53 is believed to play a pivotal role in the ability of cells to response to DNA damage, resulting in either cell cycle arrest in G1 or apoptosis under conditions of excessive damage. This growth inhibition is associated with the concomitant induction of p53 and enhanced terminal cell differentiation. In this study we evaluated the effects of PAH on cell growth, cell differentiation, xenobiotic metabolism, and DNA adduct levels in normal ectocervical epithelial cells (ECE) and compared them to cervical cells whose p53 have been inactivated either by binding to viral HPV E6 oncogene (ECE16-1) or by mutation (C33A). The PAH 3-methylcholanthrene (3MC) inhibited normal ECE and to a lesser extent ECE16-1 cell proliferation. Not only did the growth inhibition occur at lower concentrations in the normal cells but the extent of inhibition was also greater in normal as compared to immortalized cells. Benzanthracene (BA) had a minor effect on normal ECE cells with no effect on immortalized ECE16-1 cells. C33A cell growth was unaffected by 3MC and BA. Terminal cell death was enhanced only in normal ECE cells as evidenced by increased envelope formation and was paralleled by an increase in the level of p53 following 3MC treatment. The differentiation status of the 3MC-treated cells was similar to untreated cells as indicated by three independent markers of cell differentiation; transglutaminase, involucrin, keratin expression. There was no difference in the pattern or level of DNA adducts formed in normal and immortalized cells following 3MC treatment. In addition the basal level of metabolism of 14C-BaP to phenols, diols and quinnones was unaltered by pretreatment with either 3MC or BA. These results demonstrate that immortalized cervical cells are less sensitive to toxicant damage [i.e. cell proliferation and terminal differentiation], and as a result, immortalized cells proliferate in the presence of genotoxic damage and are at increased risk for mutations and cancer.
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PMID:Polycyclic aromatic hydrocarbons enhance terminal cell death of human ectocervical cells. 968 93

Two cases of mesothelial/monocytic incidental cardiac excrescences in a 66-year-old female and an 80-year-old male are presented. Lesions had solid and tubular pattern formations which were composed of two predominant cell types of histiocytoid cells and cuboidal cells arranged in strips. The histiocytoid cells were round and had well-defined nuclei with prominent nuclear grooves. They had a low nuclear to cytoplasmic ratio. There were no atypical mitoses. Immunohistochemically, these cells were positive for leukocyte common antigen (LCA) and CD68 (KP-1) but negative for keratin. The cuboidal cells were present in strips, had haphazardly arranged surface microvilli and had small round non-cleaved nuclei. These cells were positive for keratin but negative for LCA, CD68, p53, proliferative cell nuclear antigen, alpha-smooth muscle actin, Factor VIII, epithelial membranous antigen and vimentin. These lesions are probably reactive because of their heterogeneous components; an expected feature for an essentially artifactual lesion that is related to cardiac surgery and invasive catheterization. Immunohistochemical studies are useful for avoiding misdiagnosis of neoplasms.
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PMID:Two cases of mesothelial/monocytic incidental cardiac excrescences of the heart. 973 13

The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SCC). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty-two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSC]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9% developed VIN lesions and 21% invasive SCC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SCCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SCCas without LS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventional SCCa type (85% v 57%; P = .02), were associated with a prominent fibromyxoid stromal response (46% v 10%; P = .004), were not associated with VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tumor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF-beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PCNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [bc]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 bc; P < .008), and aneuploidy (33% v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P = .001), and DNA aneuploidy (52% v 11%; P = .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 bc; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SCC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both "initiator and promoter" of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.
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PMID:Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. 974 9

A new cell line, FR-car, has been established from a biopsy of a low-grade human cervical squamous intraepithelial lesion (SIL). We confirmed the epithelial origin of the cells by keratin staining using polykeratin, AE1/AE3 and CAM 5.2 antibodies. Sixty percent to 80% of the cultured cells stained positive for proliferative cell nuclear antigen (PCNA) and Ki-67. There was no overexpression of p53. Karyotyping revealed that the cell line was hypodiploid with clonal abnormalities on chromosome 6 and 16. Sections of a biopsy adjacent to the lesion from which the culture was initiated tested positive for human papillomavirus (HPV) 18 DNA by the polymerase chain reaction, but cultured cells tested at several passages were HPV-negative by either type-specific or consensus PCRs. This HPV-negative SIL line may be useful in studies into the cell biology of dysplastic epithelium.
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PMID:Characterization of an HPV-negative cell line (FR-CAR) derived from a cervical squamous intraepithelial lesion. 979 25

The histogenesis of carcinosarcoma of the breast is controversial. In the current case, the demarcation between the carcinomatous and sarcomatous components was distinct in all microscopic fields. Immunohistochemical analysis was negative for epithelial membrane antigen (EMA) and keratin in the sarcomatous component and was negative for desmin in the carcinomatous component, suggesting that this tumor could be derived from the two different stem cells. To determine the histogenesis of this tumor, both carcinomatous and sarcomatous lesions were microdissected from formalin-fixed tissues and DNAs were prepared by proteinase K digestion. PCR amplification of the human androgen receptor (HUMARA) short tandem repeat (STR), after Hpa II digestion of the genomic DNA, indicated that the patterns of X-chromosome inactivation were identical in both components. Moreover, both components contained the identical TGT --> TTT transversion in codon 275 of the p53 gene. These observations strongly support the hypothesis that this tumor is derived from a single totipotent stem cell.
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PMID:Carcinosarcoma of the breast: molecular-biological study for analysis of histogenesis. 982 16

We previously developed a transgenic mouse model that expresses in the epidermis a murine p53172R-->H mutant (p53m) under the control of a human keratin-1-based vector (HK1.p53m). In contrast to mice with wild-type p53 and p53-knockout mice, HK1.p53m mice exhibit increased susceptibility to chemical carcinogenesis, with greatly accelerated benign papilloma formation, malignant conversion, and metastasis. In the study presented here, we examined the expression pattern of several differentiation markers and observed that p53m tumors exhibited a less differentiated phenotype than tumors elicited in non-transgenic mice. Metastasis in p53m tumors was also associated with a poorly differentiated phenotype. To determine whether genomic instability was associated with a putative gain-of-function role for this p53m, in situ examination of centrosomes was performed in HK1.p53m and equivalent p53-null papillomas. In contrast to HK1.p53m papillomas, which had centrosome abnormalities at high frequencies (75% of cells contained more than three centrosomes/cell), p53-null tumors exhibited few abnormal centrosomes (4% of cells contained more than three centrosomes/cell). To determine whether angiogenesis played a role in the rapid progression of p53m tumors, the expression of vascular endothelial growth factor, a promoter of angiogenesis, and thrombospondin-1, an inhibitor of angiogenesis, was examined in tumors derived from either p53m or p53-knockout mice. Regardless of their p53 status (wild type, p53m, p53-/-), all of the papillomas exhibited similar levels of vascular endothelial growth factor expression and decreased expression of thrombospondin-1 as did normal epidermis. In addition, tumors from different p53 genotypes showed a similar density of blood vessels. Because p53 status did not appear to play an overt role in angiogenesis, these data suggest that p53m accelerates tumorigenesis primarily by exerting a gain of function associated with genomic instability.
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PMID:Analysis of centrosome abnormalities and angiogenesis in epidermal-targeted p53172H mutant and p53-knockout mice after chemical carcinogenesis: evidence for a gain of function. 983 79

In Sweden, snuff (locally known as snus), was introduced since the year 1637. Presently, Sweden has the highest per capita consumption and sale figures of snuff in the world, and the habit is becoming increasingly popular. Snus is manufactured into a dry form used in the nasal cavity and a moist form used in the oral cavity. Snus manufactured for oral use is a moist ground tobacco of Dark Kentucky or Virginia species mixed with an aqueous solution of water and other blending ingredients. This form of snuff is found in two types: (1) loose and (2) portion-bag-packed. These are the most widely used. The loose moist form (1-2 g a quid) is the most popular type consumed by 73% of the males, followed by the portion-bag-packed form (0.5-1 g a quid), consumed by 13% of the males, while 14% of the males are mixed users. The majority of snus users place the quid in the vestibular area of the upper lip, and the prevalence among persons 15 years of age or older in 15.9% among males and 0.2% among females. The pH of snus has declined from a previous range of 8-9 to a range of 7.8-8.5, moisture content ranges 35-60% and nicotine content is in the order of 5-11 mg/g dry wt tobacco-specific N-nitrosamines (TSNAs) in micrograms (N'-nitrosonornicotine: NNN 5-9; 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone: NNK 1-2; N'-nitrosoanatabine: NAT 2-5). In the Sudan, snuff, locally known as toombak, was introduced approximately 400 years ago. It is always processed into a loose moist form, and its use is widespread in the country. Tobacco used for manufacture of toombak is of the species Nicotiana rustica, and the fermented ground powder is mixed with an aqueous solution of sodium bicarbonate. The resultant product is moist, with a strong aroma, highly addictive and its use is widespread particularly among males. Its pH range is 8-11, moisture content ranges 6-60% and nicotine content is from 8 to 102 mg/g dry wt, and TSNAs contents in micrograms (NNN 420-1 550; NNK 620-7 870; NAT 20-290). Snus and toombak dippers develop a clinically and histologically characteristic lesion at the site of dipping. Probably due to control of the TSNAs in snus, this type of snuff is associated with a lower risk of cancer of the oral cavity (relative risk: RR 5-6-fold), whereas the risk for cancer of the oral cavity among toombak users was high (RR 7.3-73.0-fold). In conclusion, the two snuff products significantly differ in many aspects. Most notable differences are tobacco species, fermentation and ageing, nicotine and TSNAs content, pH, expression of the p53 tumour suppressor gene, and keratin types 13, 14, and 19. It was, therefore, the object of the present study to highlight the oral health hazards of toombak, and to compare it with snus regarding the aforementioned differences.
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PMID:The Swedish snus and the Sudanese toombak: are they different? 993 Mar 71


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