共查询到20条相似文献,搜索用时 15 毫秒
1.
Abstract: The p53 gene is mutated in numerous human cancers. We used it as a molecular target to characterize and try to understand the induction of mutations in human skin cancers. About 40–50% of all skin cancers in normal individuals and 60–80% of the DNA-repair-deficient xeroderma pigmentosum patients exhibit p53 mutations. Among these tumors, the melanomas are the less mutated ones. These mutations are characterized by specific signatures believed to be due to the UVB part of the solar spectrum. Different mutation spectra and different hot spots of mutations are found according to histopathological types of skin cancer. These data are interpreted in term of hot spots for DNA lesion induction, speed of local repair or sequence effects. The molecular analysis of these mutagenic characteristics should help us to understand the origin of human skin cancers in the general population. 相似文献
2.
Decreased p53 expression in chronically sun-exposed human skin after topical photoprotection 总被引:1,自引:0,他引:1
B. Berne J. Pontén F. Pontén 《Photodermatology, photoimmunology & photomedicine》1998,14(5-6):148-153
UV-induced DNA damage appears to play an essential role in skin car-cinogenesis. Following acute UV irradiation, there is an overexpression of normal p53 protein in epidermal keratinocytes, representing a physiological response to DNA damage. Sun protection through topical sunscreens or clothing is believed to reduce the hazardous effects of UV irradiation and subsequently the risk of skin cancer. We have examined the effect of an SPF 15 topical sunscreen and blue denim fabric (SPF 1700) in chronically sun-exposed human skin after sun exposure during a normal summer. Skin biopsies from sun-protected and sun-exposed skin were compared with respect to immunohistochemically detectable p53. This method provides a model for assessing the significance of different degrees of UV protection under physiological conditions. Our results show a significant reduction of p53-positive cells in sun-protected skin as compared with sun-exposed skin. The reduction of p53-positive keratinocytes differed between topical sunscreen (33% reduction) and blue denim fabric (66% reduction). Interindividual variations were large, possibly because of variations in sun exposure. These variations also suggest that mechanisms determining UV damage at the cellular level are complex. The role of residual p53-positive keratinocytes after 2 months of total sun-protection (i.e., SPF 1700) is discussed. 相似文献
3.
The expression of p53, p21, Bax and induction of apoptosis in normal volunteers in response to different doses of ultraviolet radiation 总被引:2,自引:0,他引:2
Murphy M Mabruk MJ Lenane P Liew A McCann P Buckley A Billet P Leader M Kay E Murphy GM 《The British journal of dermatology》2002,147(1):110-117
BACKGROUND: Ultraviolet radiation (UVR) damages keratinocytes. Direct DNA damage may undergo enzymatic repair followed by resumption of the normal cell cycle. Cells may also be eliminated without inflammation by the error-free process of programmed cell death or apoptosis. Necrosis of cells can occur after overwhelming damage. Failure of apoptosis leads to retention of cells with persistent mutations. OBJECTIVES: This study investigates p53-dependent apoptotic responses in normal skin following solar-simulated radiation (SSR). METHODS: Sun-protected buttock skin from normal volunteers with no history or clinical evidence of skin cancer was exposed to graded doses of SSR, 0.5, 1, 2 and 3 times the minimal erythema dose (MED). Biopsies taken at a range of time points (4.5, 9, 24, 33, 48 and 72 h) after UVR, quantified the time course and dose-response of apoptosis and the expression of the relevant proteins, p53, p21waf1/Cip1 and Bax, by single and double labelling techniques. RESULTS: Apoptosis was upregulated in a dose-dependent manner as was the expression of p53, p21waf1/Cip1 and Bax in response to SSR. Following exposure to 3 MEDs it was found that: (i) the maximum number of apoptotic cells occurred at 48 h; (ii) p53 protein expression was upregulated from 4 to 72 h preceding peak p21waf1/Cip1 protein expression (9-48 h) and peak Bax protein expression (33 h). CONCLUSIONS: These results suggest that, following SSR, normal human skin induces apoptosis by the p53, p21waf1/Cip1, Bax pathway in vivo. In addition, induction of apoptosis and expression of p53, p21waf1/Cip1 and Bax occurs in a dose-dependent manner. 相似文献
4.
Overexpression of cyclooxygenase-2 (COX-2) has been demonstrated in various cancers, including experimentally promoted tumors, gastrointestinal cancers, breast tumors and skin tumors. The mechanism that controls COX-2 expression is not yet clear. Currently, it is reported that COX-2 expression is frequently associated with mutated p53 genes. The goal of this study was to evaluate the expression patterns of COX-2 and p53 in several skin tumors and their correlation. An immunohistochemical method was used to investigate the expression of COX-2 and p53 proteins on formalin-fixed, paraffin-embedded tissue specimens of squamous cell carcinomas (SCC), basal cell carcinomas (BCC), Bowen's disease (BD), actinic keratosis (AK) and porokeratosis. The expression of COX-2 increased in 50% (5/10) of SCC, 80% (8/10) of BCC, 40% (4/10) of BD, 50% (5/10) of AK, and 20% (2/10) of porokeratosis cases. The expression of p53 increased in 90% (9/10) of SCC, 70% (7/10) of BCC, 70% (7/10) of BD, 50% (5/10) of AK, and 40% (4/10) of porokeratosis cases. COX-2 positivity rates of the p53-positive skin tumors were 56%, 100%, 57%, 80% and 25% in SCC, BCC, BD, AK and porokeratosis, respectively. However, the correlation between p53 and COX-2 expression in skin tumors was not statistically significant ( P > 0.05). Our results indicate that skin COX-2 and p53 may play roles in skin tumors, but that there is no apparent correlation between the two markers. 相似文献
5.
Heitzer E Seidl H Bambach I Schmidbauer U Cerroni L Wolf P 《Experimental dermatology》2012,21(4):277-280
Keloids are characterized by extreme fibroblastic overgrowth of unknown pathogenesis after skin injury. Previous studies, mostly in non-Caucasian populations, suggest that p53 mutations may be involved. To substantiate this, we performed DNA sequence analysis of exons 4-8 of the p53 gene and immunohistochemical staining of p53 protein in archived keloidal tissue samples from 23 Caucasian patients. In contrast to previous reports, we found mutated p53 in keloidal tissue in a minority of cases (2/23; 12%). The G allele frequency and C allele frequency at the p53 polymorphic codon 72 were 0.72 (33/46) and 0.28 (13/46), respectively, in our study, a finding that was similar to the 0.77 (184/240) vs. 0.23 (56/240) (P = 0.4580; chi-squared test) observed in the Hap Map data of a European population but statistically significantly different from the 0.43 (547/1258) vs. 0.57 (711/1258) (P = 0.0002; chi-squared test) observed in the 1000 Genome project [Database of Single Nucleotide Polymorphisms (dbSNP). Bethesda (MD): National Center for Biotechnology Information, National Library of Medicine. dbSNP accession:rs1042522, (dbSNP Build ID: 132). Available from: (http://www.ncbi.nlm.nih.gov/SNP/] a difference most likely due to the different genetic background of the populations enrolled. However, one-third of the keloidal samples showed lesional nuclear p53 staining with a UV penetration gradient-like positivity (P ≤ 0.0084). Staining with an anti-cyclobutane pyrimidine dimer antibody revealed the total absence of short-term photoproducts in the epidermis as well as keloidal tissue. Furthermore, all fibroblasts expressing p53 stained negative for Ki-67, indicating that these cells were in a quiescent stage and p53 upregulation did not contribute to keloidal proliferation. We conclude that p53 plays no major role in the pathogenesis of keloids in the Caucasian population. 相似文献
6.
Roles of the transcription factor p53 in keratinocyte carcinomas 总被引:1,自引:0,他引:1
D. E. Brash 《The British journal of dermatology》2006,154(S1):8-10
7.
Background Mitochondrial DNA (mtDNA) displacement-loop (D-loop) mutations have previously demonstrated potential as smoking-induced biomarkers in oral squamous cell carcinoma (SCC). Additionally, they have been observed in SCC and basal cell carcinoma of nonmelanoma skin cancer (NMSC). However, they have not been examined in the SCC precursor lesions, Bowen disease or actinic keratosis.
Objectives Here, we present a novel study of mtDNA D-loop mutations in these two precursors, a rare keratoacanthoma and NMSC (all tumours not related to smoking).
Methods We used a polymerase chain reaction and direct sequencing approach. Furthermore, as the tumour suppressor protein p53 has been reported as having a novel role in maintaining mitochondrial genetic stability, we assessed p53 status using immunohistochemistry, evaluating potential association with the presence of mtDNA mutations.
Results Of 36 tumours, nine (25%) exhibited mutations in the D-loop. In total, 13 base substitutions were observed across all patients: seven (53·8%) were A : T to G : C; two (15·4%) were G : C to T : A; two (15·4%) were G : C to A : T and two (15·4%) were G : C to C : G. Four of the 13 (30·8%) base substitutions were observed at nucleotide 146. We observed abnormal p53 accumulation in over half of the samples analysed (55·5%), suggesting it to be a major part of the carcinogenic process of NMSC; however; there was no association between p53 positivity and the presence of mtDNA mutations ( P = 0·47).
Conclusions It is unlikely that alteration in p53 status is a contributing factor to mtDNA mutagenesis. 相似文献
Objectives Here, we present a novel study of mtDNA D-loop mutations in these two precursors, a rare keratoacanthoma and NMSC (all tumours not related to smoking).
Methods We used a polymerase chain reaction and direct sequencing approach. Furthermore, as the tumour suppressor protein p53 has been reported as having a novel role in maintaining mitochondrial genetic stability, we assessed p53 status using immunohistochemistry, evaluating potential association with the presence of mtDNA mutations.
Results Of 36 tumours, nine (25%) exhibited mutations in the D-loop. In total, 13 base substitutions were observed across all patients: seven (53·8%) were A : T to G : C; two (15·4%) were G : C to T : A; two (15·4%) were G : C to A : T and two (15·4%) were G : C to C : G. Four of the 13 (30·8%) base substitutions were observed at nucleotide 146. We observed abnormal p53 accumulation in over half of the samples analysed (55·5%), suggesting it to be a major part of the carcinogenic process of NMSC; however; there was no association between p53 positivity and the presence of mtDNA mutations ( P = 0·47).
Conclusions It is unlikely that alteration in p53 status is a contributing factor to mtDNA mutagenesis. 相似文献
8.
Green tea extract reduces induction of p53 and apoptosis in UVB-irradiated human skin independent of transcriptional controls 总被引:1,自引:0,他引:1
Mnich CD Hoek KS Virkki LV Farkas A Dudli C Laine E Urosevic M Dummer R 《Experimental dermatology》2009,18(1):69-77
Ultraviolet (UV) irradiation plays a pivotal role in human skin carcinongenesis. Preclinically, systemically and topically applied green tea extract (GTE) has shown reduction of UV-induced (i) erythema, (ii) DNA damage, (iii) formation of radical oxygen species and (iv) downregulation of numerous factors related to apoptosis, inflammation, differentiation and carcinogenesis. In humans, topical GTE has so far only been tested in limited studies, with usually very high GTE concentrations and over short periods of time. Both chemical stability of GTE and staining properties of highly concentrated green tea polyphenols limit the usability of highly concentrated green tea extracts in cosmetic products. The present study tested the utility of stabilized low-dose GTE as photochemopreventive agents under everyday conditions. We irradiated with up to 100 mJ/cm(2) of UVB light skin patches which were pretreated with either OM24-containing lotion or a placebo lotion. Biopsies were taken from both irradiated and un-irradiated skin for both immunohistochemistry and DNA microarray analysis. We found that while OM24 treatment did not significantly affect UV-induced erythema and thymidine dimer formation, OM24 treatment significantly reduced UV-induced p53 expression in keratinocytes. We also found that OM24 treatment significantly reduced the number of apoptotic keratinocytes (sunburn cells and TUNEL-positive cells). Carefully controlled DNA microarray analyses showed that OM24 treatment does not induce off-target changes in gene expression, reducing the likelihood of unwanted side-effects. Topical GTE (OM24) reduces UVB-mediated epithelial damage already at low, cosmetically usable concentrations, without tachyphylaxis over 5 weeks, suggesting GTE as suitable everyday photochemopreventive agents. 相似文献
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变性梯度凝胶电泳和单链构象多态性分析检测皮肤癌p16、p53基因突变 总被引:2,自引:0,他引:2
目的:探讨p16、p53基因突变在皮肤癌发生中的作用并比较变性梯度凝胶电泳(DGGE)和单链构象多态性分析(SSCP)检测基因突变的敏感性。方法:分别采用聚合酶链反应(PCR)-DEEG和PCR—SSCP,对40例皮肤癌患者手术切除组织的p16基因1、2外显子和p53基因5~8外显子进行突变检测。结果:仅2例鳞状细胞癌(SCC)出现p16基因外显子2突变,皮肤癌p16基因1、2外显子的突变率为5%。p53基因5—8外显子的突变率为35%,其中SCC的突变率为36%,基底细胞癌(BCC)为33%,采用DGGE检测的突变率为33%,SSCP检测的突变率为25%。结论:p16、p53基因突变参与皮肤癌的发病机制;p16基因的突变率低于p53基因;DGGE检测基因突变的敏感性高于SSCP;DGGE结合SSCP有助于提高突变检出率。 相似文献
11.
Frank R. de Gruijl 《Experimental dermatology》2002,11(S1):37-39
Abstract: The epidermis is excellently adapted to the sun's ultraviolet (UV) radiation. The p53 protein plays a crucial role in the orchestration of a cell's response to UV-induced damage, and more specifically to DNA damage. This response appears to differ between differentiated (suprabasal) and undifferentiated (basal) epidermal cells. The latter are the most likely targets in UV carcinogenesis. The UVB-related mutations in p53 genes of human carcinomas from sun-exposed skin indicate that rendering p53 dysfunctional is an important (early) step in the formation of these tumors. Experiments in hairless mice confirm this finding for UVB-driven carcinogenesis, but not for UVA1-(365-nm)-driven carcinogenesis. Microscopic clusters of preneoplastic cells overexpressing mutant p53 occur in chronically UVB-exposed murine skin long before the ultimate carcinomas. The number of these clusters at a certain time-point appears to be predictive of the tumor risk at latter time-points. These UVB-induced p53 clusters appear to be suitable surrogates of tumors in short-term experiments. 相似文献
12.
Inês Alencar de Castro Larissa Schütz Edison Capp ré Cartell Luise Meurer & Lucio Bakos 《Photodermatology, photoimmunology & photomedicine》2009,25(2):106-108
In non-melanoma skin cancer, keratinocytes show marked p53 protein expression. Considering photoaging as a background for skin cancer, p53 protein expression by immunohistochemistry was evaluated in normal skin with different levels of photoaging. The difference in p53 expression between mild and severe levels of photoaging was not statistically significant ( P =0.169). 相似文献
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Ultraviolet radiation (UVR) plays an important role in the development of non-melanoma skin cancer. Most tumors develop in chronically sun-exposed skin, most often in cosmetically sensitive locations, where in vivo experiments may be difficult to perform. In this study, we describe a skin organ culture model with preserved normal morphology and intact response to UVR. Skin explants from chronically sun-exposed and non-sun-exposed skin were irradiated with artificial UVA+UVB with and without topical sunscreen. UV-induced DNA damage, epidermal p53 response and repair kinetics were analyzed using immunohistochemistry. Four hours after UV-irradiation epidermal keratinocytes showed a strong immunoreactivity for thymine-dimers. Gradual repair during an incubation time resulted in few residual thymine-dimers after 48 h. Repair appeared to be more efficient in chronically sun-exposed skin compared with non-sun-exposed skin. There was also an accumulation of p53 protein in epidermal keratinocytes, peaking at 4-24 h after irradiation. Large interindividual differences with respect to formation and repair of thymine-dimers as well as induction and duration of the p53 response were observed. Skin explants treated with topical sunscreen prior to UV-irradiation showed a clear reduction of thymine-dimers and p53 expression. The epidermal UV-responses and repair kinetics in organ-cultured skin were similar to what was found in vivo. Our data suggest that organ-cultured skin provides a valuable tool for studies of UV-induced epidermal responses in chronically sun-exposed skin. 相似文献
15.
AJ Stratigos† N Kapranos‡ E Petrakou‡ A Anastasiadou‡ A Pagouni† E Christofidou† A Petridis† O Papadopoulos† E Kokka‡ C Antoniou† S Georgala† AD Katsambas† 《Journal of the European Academy of Dermatology and Venereology》2005,19(2):180-186
BACKGROUND: Sunlight precipitates a series of genetic events that lead to the development of skin cancers such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The p53 tumour suppressor gene, which plays a pivotal role in cell division and apoptosis, is frequently found mutated in sunlight-induced skin tumours. OBJECTIVE: To investigate the immunoreactivity of the p53 gene in non-melanoma skin cancers and to correlate its expression with apoptotic and cell proliferation markers. METHODS: We analysed 35 non-melanoma tumours including 19 BCCs and 16 SCCs from sun-exposed skin areas. p53 protein expression was studied immunohistochemically using the DO7 monoclonal antibody against wild-type and mutant p53 forms. The percentage of p53-immunopositive nuclei was measured by image analysis. Cell proliferation and apoptosis were also assessed by image analysis following Ki-67 immunostaining and application of the TUNEL method on paraffin sections, respectively. RESULTS: The percentage of p53-expressing cells varied from 3.5 to 90 in BCCs (median value 54.4%) and from 3.7 to 94 in SCCs (median value 40.3%). The mean value of Ki-67-positive cells was comparable in both groups of tumours with a mean value of 40.6% in BCCs and 34.6% in SCCs. Conversely, the TUNEL assay showed sporadic staining of apoptotic cells within the tumours with a mean value of 1.12% in BCCs and 1.8% in SCCs. p53 protein expression was correlated positively with cell proliferation (r = 0.75, P = 0.000001) and negatively with apoptosis (r = -0.23, P = 0.05). CONCLUSION: p53 immunoreactivity was high in the majority of the skin carcinomas examined and correlated positively with cell proliferation and negatively with apoptosis. The p53 protein overexpression appears to be related to an inactivated protein resulting from mutations of the p53 gene or other unclear molecular mechanisms. 相似文献
16.
Youn CS Kwon OS Hwang EJ Jo SJ Lee MJ Lee HS Chung JH 《Photodermatology, photoimmunology & photomedicine》2005,21(4):198-203
Background/Purpose: As most biochemical systems are affected by temperature, thermal changes before or after ultraviolet (UV) irradiation could influence skin vascular blood flow changes and inflammatory responses. In this study, our aim was to investigate the influence of thermal changes on UV-induced acute skin reactions, namely, erythema and pigmentation.
Methods: Our volunteers consisted of 10 males, with ages ranging from 22 to 24 years and with Fitzpatrick's skin type III or IV. Skin temperatures were changed with a 45°C heating pad or by ice pack application before or after UV irradiation (control, 1 minimal erythema dose (MED), 2 MED) and then changes in erythema and pigmentation were measured by a Minolta Spectrophotometer CM-2002.
Results: The present study demonstrates that both heating and cooling increase skin erythema and reduce pigmentation, and that the timing of heating and cooling influences the UV-induced skin reaction. Pre-heating and post-cooling groups showed more UV-induced erythema than the post-heating and pre-cooling groups, respectively.
Conclusion: Our results indicate that alteration of skin surface temperature could modulate UV-induced erythema and pigmentation responses. 相似文献
Methods: Our volunteers consisted of 10 males, with ages ranging from 22 to 24 years and with Fitzpatrick's skin type III or IV. Skin temperatures were changed with a 45°C heating pad or by ice pack application before or after UV irradiation (control, 1 minimal erythema dose (MED), 2 MED) and then changes in erythema and pigmentation were measured by a Minolta Spectrophotometer CM-2002.
Results: The present study demonstrates that both heating and cooling increase skin erythema and reduce pigmentation, and that the timing of heating and cooling influences the UV-induced skin reaction. Pre-heating and post-cooling groups showed more UV-induced erythema than the post-heating and pre-cooling groups, respectively.
Conclusion: Our results indicate that alteration of skin surface temperature could modulate UV-induced erythema and pigmentation responses. 相似文献
17.
Jasim ZF Lioe TF McKenna KE Robson T Ouhtit A 《Photodermatology, photoimmunology & photomedicine》2006,22(1):12-17
BACKGROUND: Psoriasis is a genetically determined inflammatory skin disease. It is now recognized that narrow band TL-01 phototherapy is an effective treatment for psoriasis. However, ultraviolet (UV) exposure induces p53 mutations in keratinocytes and repeated exposure of skin to UV radiation results in clonal expansion of these initiated p53-mutant cells within the epidermis. AIM: The present study aims to examine epidermal p53 expression in the skin of psoriatic patients at different time points following TL-01 phototherapy. METHODS: Skin samples from patients suffering from plaque-type psoriasis, collected before, during and at the final stages of TL-01 phototherapy were examined for p53 expression by immunohistochemistry. RESULTS/CONCLUSION: Our results showed an increase in p53 expressing keratinocytes following TL-01 phototherapy. Some of these cells were arranged spatially, as conical clones arising from putative stem cell compartments, suggesting that the chronic TL-01 treatment might have triggered cell growth and clonal expansion, an important step in initiating skin carcinogenesis. 相似文献
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Differential p53-mediated responses to solar-simulated radiation in human papillomavirus type 16-infected keratinocytes 总被引:1,自引:1,他引:0
In immunocompromised patients, cooperative effects of human papillomavirus (HPV) and ultraviolet (UV) radiation have been postulated in the development of non-melanoma skin cancers. The tumor suppressor p53 is a key component of the cellular response to genotoxic agents, such as UV radiation. We have previously demonstrated that in HPV16-infected cells, a higher E6* level was associated with a higher resistance to UV and oxidative stress. Using the two same SKv cell lines, the aim of the present study was to investigate p53 and p21 expression and cell death in HPV-infected keratinocytes in response to UV irradiation and to determine the role of HPV oncoprotein levels on the p53-mediated cellular response. We demonstrated that the weakly E6*-expressing level SKv-e cell line presented both higher cytotoxicity and apoptosis to UV. This high sensitivity was associated with both p53 and p21 nuclear accumulation, while a high E6* level and resistance were associated with no p53 accumulation and a p21 nuclear down-regulation after UV. Moreover, in SKv-e cell line, p21 promoter activation was p53 dependent. Our results suggest that an alteration and/or a modulation of the p53-p21 pathway in response to UV could be determinant for HPV-infected keratinocyte survival and HPV-associated carcinogenic process. 相似文献
20.
BACKGROUND AND OBJECTIVES: This preliminary laboratory-based study looks at the paracrine release from human skin cells subject to sublethal Q-switched Nd:YAG 532 nm laser irradiation. STUDY DESIGN/MATERIALS AND METHODS: Human dermal fibroblast and keratinocyte cultures were exposed to sublethal energy using the Nd:YAG 532 nm laser. Altered gene expression was then screened using RT-PCR for a range of paracrine factors known to affect melanogenesis, basic fibroblast growth factor (b-FGF), hepatocyte growth factor (HGF), stem cell factor (SCF), melanocyte stimulating hormone (MSH), endothelin-1 (ET-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and protease-activated receptor-2 (PAR-2). Enzyme-linked immunosorbent assay (ELISA) was used to confirm protein production. Conditioned medium was used to assess altered melanogenesis in a melanoma cell line. Results: Fibroblasts exposed to sublethal radiation showed upregulation of b-FGF, HGF and SCF. This contrasts with keratinocytes which showed upregulation of IL-6. Elevated protein levels of b-FGF and SCF were confirmed by ELISA assay. Conditioned fibroblast medium was shown to stimulate melanogenesis in a melanoma cell line. CONCLUSIONS: This preliminary laboratory study reports, for the first time, specific gene upregulation using the Q-switched Nd:YAG 532 nm laser. 相似文献