UNIPROT:P04637 - FACTA Search

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

The expression of C-myc p62, bcl-2, p53, PCNA and EBV-encoded LMP-1 proteins was studied by immunohistochemistry on paraffin-embedded skin specimens from 14 patients with early stage (premycotic erythema and second stage plaques) mycosis fungoides (MF), 21 patients with advanced stage MF (third stage plaques and tumors), 3 patients with Sezary's syndrome (SS) and 3 patients with pleomorphic medium and large cell cutaneous T-cell lymphomas (PML-CTCL). All 41 cases were also screened for the presence of EBV by using RNA in situ hybridization with EBER 1/2 oligonucleotides. Increased expression of C-myc p62, p53 and PCNA proteins was found in PML-CTCL and advanced stages of MF as compared to early stages of MF. These results suggest a relationship between levels of C-myc p62, p53 and PCNA proteins and aggressiveness of the cutaneous T-cell lymphomas. Furthermore, C-myc p62 and bcl-2 proteins were found to be frequently coexpressed in the present series. In view of the background information from in vitro findings and animal models that cooperation of C-myc and bcl-2 is important for lymphomagenesis, our results suggest that coexpression of these oncogenes may be implicated in the pathogenesis and/or the progression of cutaneous T-cell lymphomas. Neither LMP-1 expression nor EBV EBER l/2 transcripts were detected in our series suggesting that EBV is not involved in the pathogenesis of cutaneous T-cell lymphomas.
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PMID:Mycosis fungoides: expression of C-myc p62 p53, bcl-2 and PCNA proteins and absence of association with Epstein-Barr virus. 783 Nov 52

The mechanisms mediating the varied effects of ultraviolet radiation (UVR) on human skin are unclear, although a relationship between erythema and DNA damage is suggested by photosensitivity in xeroderma pigmentosum. Increased p53 expression in response to UVR is thought to reflect direct DNA damage, but recent evidence indicates that UVR also activates membrane and cytosolic signal transduction pathways. In this study, we have investigated the relationship between erythema and p53 induction following UVB and whether this p53 response is specific to UVR. p53 protein expression was determined by immunocytochemistry using the monoclonal antibody DO7, and p53 mRNA expression was examined by non-isotopic in situ hybridization. Incremental doses of UVB were administered to the lower back of eight subjects. Immunostaining revealed that p53 positive nuclei were significantly increased 8 h after suberythemogenic doses of UVB (79 +/- 12), compared to normal unirradiated skin (8 +/- 6, p < 0.0005), but no change in p53 mRNA was seen. Higher UVB doses, which resulted in moderate erythema, resulted in a similar or greater induction of p53 protein. Indomethacin (1% w/v), applied immediately after UVB irradiation, significantly inhibited UVB erythema at 8 h in six subjects (p < 0.005), but did not reduce p53 immunostaining. Dithranol (1 microgram/microliter, n = 8), sodium dodecylsulphate (5%, n = 4), and retinoic acid (0.5%, n = 4), applied for 48 h, caused erythema, significantly increased p53 protein levels (p < 0.05), and also increased p53 mRNA. Our results show that in human skin, UVB-induced p53 elevation can be dissociated from erythema and skin irritants can also induce p53 protein. The induction of p53 mRNA by irritants but not UVR suggests different mechanisms of action.
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PMID:Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, and induction of p53 protein and mRNA following application of skin irritants. 793 Jun 73

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a mutation-prone (G:C to T:A transversion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversions are observed in the p53 and ras genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sunlight. In the current study, 8-OHdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m2 of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OHdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OHdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OHdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogenesis.
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PMID:8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure. 887 58

It is generally presumed that xeroderma pigmentosum (XP) patients are extremely sensitive to developing UV erythema, and that they have a more than 1000-fold increased skin cancer risk. Recently established mouse models for XP can be employed to investigate the mechanism of these increased susceptibilities. In line with human data, both XPA and XPC knockout mice have been shown to have an increased susceptibility to UVB induced squamous cell carcinomas. In XPA knockouts, nucleotide excision repair of UV induced DNA photolesions is completely defective (i.e., both global genome repair and transcription coupled repair are defective). We determined the strand specific removal of cyclobutane pyrimidine dimers and pyrimidine [6-4] pyrimidone photoproducts from the p53 gene in cells from XPC knockout mice and wild-type littermates. Analogous to human XPC cells, embryonic fibroblasts from XPC knockout mice are only capable of performing transcription coupled repair of DNA photolesions. We show that these XPC knockout mice, in striking contrast to XPA knockout mice, do not have a lower minimal erythema/edema dose than their wild-type littermates. Hence, defective global genome repair appears to lead to skin cancer susceptibility, but does not influence the sensitivity to acute effects of UVB radiation, such as erythema and edema. The latter phenomena thus relate to the capacity to perform transcription coupled repair, which suggests that blockage of RNA synthesis is a key event in the development of UV erythema and edema.
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PMID:Defective global genome repair in XPC mice is associated with skin cancer susceptibility but not with sensitivity to UVB induced erythema and edema. 954 Sep 83

Skin cancers are among the most common human cancers and have an increasing incidence. The ultraviolet radiation components of sunlight play a major role in skin tumor induction and development. Cellular DNA has been identified as a target for most of the biological effects of UV, and the induction of photodamage is considered as the initiating step of photocarcinogenesis. Thus, effective photoprotection of DNA against harmful overex-posure to solar UV is a critical issue. The efficiency of a sunscreen is usually tested with respect to its ability to prevent skin erythema, but conceivably, more data are required at the molecular and cellular level in order to ascertain protection against photocarcinogenic risk. In the present study, we define a strategy based on the use of various in vitro models and solar-simulated light to evaluate photodamage and photoprotection: -Supercoiled circular plasmid DNA for detection of structural alterations. -The yeast Saccharomyces cerevisiae to evaluate cytotoxicity and genotoxicity. -The single-cell gel electrophoresis or comet assay to determine DNA damage and DNA repair in human keratinocytes. -p53 expression as a hallmark for genotoxic stress. -Induction of pigmentation in human melanocytes. In conditions where light source, spectrum and control of radiation delivery were precisely defined, we have demonstrated that the wide spectrum UVA sunscreen Mexoryl SX protects from the cytotoxicity and genotoxicity of solar UV.
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PMID:An in vitro strategy to evaluate the phototoxicity of solar UV at the molecular and cellular level: application to photoprotection assessment. 972 50

Exposure of normal human breast skin ex vivo to physiological levels of UV-B and solar simulated UV results in a UV dose- and time-dependent increase in epidermal p53, as determined by PAGE analysis. Peak p53 levels are detected 12 to 24 h post irradiation with UV-B (470-1410 mJ cm-2) and solar simulated UV (5-12 minimal erythema dose (MED) equivalents). Irradiation with an FS20 UV-B lamp, contaminated with UV-A and UV-C (74-1111 mJ cm-2), also induces peak levels after 12 h incubation at 37 degrees C but these levels persist to 36 h post UV irradiation. In all cases p53 levels start to return to normal by 48 h culture. A significant positive correlation is demonstrated between UV-B dose (47-1645 mJ cm-2) and p53 level (p < 0.01, R > 0.977) in explants cultured for 24 h at 37 degrees C post irradiation. The FS20 induces a 'UV-B' dose-dependent increase in p53 to a maximum from 370 to 1111 mJ cm-2. Similarly, solar simulated UV induces a plateau of peak p53 induction between 5 and 15 MED equivalents. Immunohistochemical analysis using microwave retrieval on 5 microns sections shows the same pattern of p53 staining with UV-B and solar UV insult, but proves unreliable as a method of quantification. These results suggest that the skin explant model may be a useful tool in the evaluation of UV-induced epidermal cell damage, providing a valuable alternative to in vivo studies.
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PMID:p53 induction in normal human skin in vitro following exposure to solar simulated UV and UV-B irradiation. 1039 67

The step of intravasation or lymphovascular invasion can be a rate-limiting step in the metastatic process. Inflammatory breast carcinoma manifests an exaggerated degree of lymphovascular invasion in situ; hence, a study of its molecular basis might shed light on the general mechanism of lymphovascular invasion exhibited by all metastasizing cancers. To this end, we have established the first human transplantable inflammatory breast carcinoma xenograft (MARY-X) in scid/nude mice. Whereas all other human xenografts grew as isolated s.c. nodules, MARY-X grew exclusively within murine lymphatics and blood vessels, and these latter elements and their supporting stroma comprised, by murine Cot-1 DNA analysis, 30% of the tumor. MARY-X, like its human counterpart, exhibited striking erythema of the overlying skin. MARY-X was estrogen receptor, progesterone receptor, Her-2/neu negative and p53, epidermal growth factor receptor positive. The primary tumor of origin of MARY-X exhibited identical markers, except that about 50% of its cells exhibited Her-2/neu amplification. Comparative studies of MARY-X with noninflammatory xenografts indicated 10-20-fold overexpression of E-cadherin and MUC1, findings that were reflected in actual cases of human inflammatory breast cancer. MARY-X should allow us to further dissect out both the upstream regulatory machinery and the downstream effector molecules responsible for the inflammatory carcinoma phenotype.
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PMID:A novel human xenograft model of inflammatory breast cancer. 1053 77

In previous studies, we showed that green tea and black tea extracts and their major polyphenolic constituents protect against UVB light-induced carcinogenesis in murine skin. All of these studies required chronic administration of tea extracts or specific constituents either topically or orally. However, it is not known whether acute or subchronic administration of black tea extracts or constituents can ameliorate UVB-induced early effects in skin. In the present study, cultured keratinocytes and mouse and human skin were employed to assess the effect of both oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic subfractions namely BTF1 and BTF2 against UVB-induced photodamage. In SKH-1 hairless mice, topical application of SBTE (0.2 mg/cm2) prior to UVB exposure (180 mJ/cm2) resulted in 40% reduced incidence and 64% reduced severity of erythema and 50% reduction in skinfold thickness by day 6 when compared to nontreated UVB-exposed animals. The SBTE was also effective in protecting against UVB-induced erythema in human volunteers. Administration of SBTE 5 min after UVB irradiation was similarly effective in reducing UVB-induced inflammation in both murine and human skin. The major polyphenolic subfractions, BTF1 and BTF2, were also effective in protecting in mouse skin. The SBTE subfractions inhibited UVB-induced tyrosine phosphorylation of epidermal growth factor receptor (EGFR). The UVB irradiation of human epidermoid carcinoma cells resulted in 3.3-fold induction of tyrosine phosphorylation of EGFR. Pretreatment with BTF1 and BTF2 reduced tyrosine phosphorylation of EGFR by 53% and 31%, respectively. The UVB-mediated enhanced expression of the early response genes, c-fos and c-jun in human epidermal keratinocytes was reduced in a dose-dependent manner by SBTE. Topical application of SBTE was also effective in reducing accumulation of c-fos and p53 proteins by 82% and 78%, respectively, in UVB-exposed mouse skin. These data provide evidence that constituents of black tea can abrogate UVB-induced erythema and associated early events in murine and human skin.
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PMID:Photoprotective effect of black tea extracts against UVB-induced phototoxicity in skin. 1054 58

The use of psoralens combined with exposure to ultraviolet A radiation is a major form of treatment for psoriasis and a number of other common skin diseases. Although psoralen plus ultraviolet A treatment is highly effective, careful follow-up cohort studies have shown that it greatly increases risk for the development of cutaneous squamous cell carcinoma and melanoma. Strategies to reduce the risk of cancer development in psoralen plus ultraviolet A-treated populations are highly desirable. In prior studies, we demonstrated that green tea and constituent polyphenols protect against ultraviolet B-induced carcinogenesis and reduce the growth rate of established tumors in skin. In this study, we show that pre- and post-treatment with standardized green tea extract in psoralen plus ultraviolet A treatment populations abrogates the psoralen plus ultraviolet A-induced photochemical damage to skin. Intact mouse and human skin and reconstituted human skin were employed to assess the effect of both topical and oral administration of standardized green tea extract against psoralen plus ultraviolet A-induced photodamage. Oral administration of standardized green tea extract prior to and during multiple psoralen plus ultraviolet A treatments reduced hyperplasia and hyperkeratosis in murine skin. Standardized green tea extract treatment also inhibited accumulation of c-fos and p53 protein induction following a single exposure to psoralen plus ultraviolet A. c-fos and p53 positive cells in psoralen plus ultraviolet A-treated skin were found to be increased by 55.4 +/- 13. 6% and 62.3 +/- 10.5%, respectively, compared with saline-treated unexposed control skin. Oral administration of 0.4 or 0.8% standardized green tea extract inhibited c-fos protein accumulation by 18.5% and 46.2% (p < 0.05), respectively, and p53 protein accumulation by 26.1% and 54.3% (p < 0.05), respectively. Similarly proliferating cell nuclear antigen staining, a marker of cell proliferation was induced (73.7%) in psoralen plus ultraviolet A-treated skin. Oral administration of 0.4% or 0.8% standardized green tea extract 1 d after psoralen plus ultraviolet A treatment was effective in reducing psoralen plus ultraviolet A-induced inflammatory responses including erythema and edema formation. When standardized green tea extract was applied to EpiDerm, a reconstituted human skin equivalent, psoralen plus ultraviolet A-induced 8-methoxypsoralen-DNA adduct formation and p53 protein accumulation were inhibited. Topical application of 0.2 mg 8-methoxypsoralen per cm2 followed by exposure to ultraviolet A (2.5 J per cm2) resulted in delayed erythema formation in human subjects. Pretreatment of human skin with topical application of 0.2 mg standardized green tea extract per cm2 30 min prior to psoralen plus ultraviolet A treatment resulted in an almost complete abrogation of psoralen plus ultraviolet A-induced erythema. In summary, these data demonstrate that standardized green tea extract protects against psoralen plus ultraviolet A-induced phototoxicity by inhibiting DNA damage and diminishing the inflammatory effects of this modality.
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PMID:Green tea protects against psoralen plus ultraviolet A-induced photochemical damage to skin. 1059 54

Protection against sun-induced damage leading to photocarcinogenesis in skin is a highly desirable goal. Among various strategies, chemopreventive approaches utilizing non-toxic agents to prevent the occurrence of precancerous lesions or their surrogate markers are potentially attractive. Epidemiological and experimental studies provide evidence that some naturally occurring chemical agents in the human diet can diminish cancer risk. Aside from water, tea is the most common beverage consumed worldwide. Black tea accounts for nearly 80% of total tea production. Black tea and green tea are derived from the same plant, Camelia sinensis. Green tea contains monomeric polyphenols known as flavanols and black tea contains dimeric flavanols and polymeric polyphenols known as theaflavins (TFs) and thearubigins (TRs). Over the past fifteen years our laboratory has been exploring the feasibility of using tea and its constitutents as an approach to skin cancer prevention. We demonstrated that green tea, black tea and constituent polyphenols protect against chemical- and ultraviolet B (UVB)-induced carcinogenesis and reduce the growth of established tumors in skin. We have also shown the efficacy of green and black tea extracts against UVB and psoralen + ultraviolet A (PUVA)-induced early damage in skin. Although PUVA is highly effective in treating certain skin diseases, careful follow-up studies of cohorts of patients have shown that similar to UVB, PUVA treatment increases the risk for cutaneous squamous cell carcinoma and melanoma. We have found that oral administration of a standardized green tea extract (SGTE) prior to and during treatment of SKH-1 mice diminished PUVA-induced skin hyperplasia and hyperkeratosis. SGTE-treatment also inhibited PUVA-induced accumulation of c-fos and p53 proteins and epithelial hyperproliferation. Both topical application and oral administration of SGTE after PUVA-treatment reduced skin inflammation and cell hyperproliferation. Topical application of SGTE to human skin prior to PUVA-treatment inhibited the delayed skin inflammatory response. Similarly, oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic sub-fractions protect against UVB-induced erythema in SKH-1 mice. Furthermore, topical application of tea extracts to human volunteers protects against UVB-induced erythema. In summary, these studies indicate that tea extracts are effective in reducing UVB- and PUVA-mediated DNA damage, expression of early response genes and early inflammatory changes in skin. These studies verify a conceptual rationale for employing naturally occurring dietary constitutents as an approach to cancer chemoprevention.
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PMID:Novel approaches to chemoprevention of skin cancer. 1113 32

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