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)

p53 mutations appear to be early events in skin carcinogenesis induced by chronic UVB irradiation. Clusters of epidermal cells that express p53 in mutant conformation ("p53 positive foci") are easily detected by immunohistochemical staining long before the appearance of skin carcinomas or their precursor lesions. In a hairless mouse model, we determined the dose-time dependency of the induction of these p53+ foci and investigated the relationship with the induction of skin carcinomas. The density of p53+ foci may be a good direct indicator of tumor risk. Hairless SKH1 mice were exposed to either of two regimens of daily UVB (500 or 250 J/m2 broadband UV from Philips TL12 lamps; 54% UVB 280-315 nm). With the high-dose regimen, the average number of p53+ foci in a dorsal skin area (7.2 cm2) increased rapidly from 9.0 +/- 2.1 (SE) at 15 days to 470 +/- 80 (SE) at 40 days. At half that daily dose, the induction of p53+ foci was slower by a factor of 1.49 +/- 0.15, very similar to a previously observed slower induction of squamous cell carcinomas by a factor of 1.54 +/- 0.02. In a double-log plot of the average number of p53 + foci versus time, the curves for the two exposure regimens ran parallel (slope, 3.7 +/- 0.7), similar to the curves for the number of tumors versus time (slope, 6.9 +/- 0.8). The difference in slopes (3.7 versus 6.9) is in line with the contention that more rate-limiting steps are needed to develop a tumor than a p53+ focus. By the time the first tumors appear (around 7-8 weeks with the high daily dose), the dorsal skin contains >100 p53+ foci/cm2. To further validate the density of p53+ foci as a direct measure of tumor risk, we carried out experiments with transgenic mice with an enhanced susceptibility to UV carcinogenesis, homozygous Xpa knockout mice (deficient in nucleotide excision repair) and heterozygousp53 knockout mice (i.a. partially deficient in apoptosis). In both of these cancer-prone strains, the p53+ foci were induced at markedly increased rates, corresponding to increased rates of carcinoma formation. Therefore, the frequency of p53+ foci appears to correlate well with UVB-induced tumor risk.
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PMID:Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity. 1122 93

Although epidemiological evidence shows an association between arsenic in drinking water and increased risk of skin, lung, and bladder cancers, arsenic compounds are not animal carcinogens. The lack of animal models has hindered mechanistic studies of arsenic carcinogenesis. Previously, this laboratory found that low concentrations of arsenite (the likely environmental carcinogen) which are not mutagenic can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR). This enhancing effect appears to result from inhibition of DNA repair by arsenite. Recently we found that low concentrations of arsenite disrupted p53 function and upregulated cyclin D1. These results suggest that the failure to find an animal model for arsenic carcinogenesis is because arsenite is not a carcinogen per se, but rather acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR as carcinogenic stimulus in hairless Skh1 mice. Mice given 10 mg/l sodium arsenite in drinking water for 26 weeks had a 2.4-fold increase in yield of tumors after 1.7 KJ/m(2) UVR three times weekly compared with mice given UVR alone. No tumors appeared in mice given arsenite alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite appeared earlier and were much larger and more invasive than in mice given UVR alone. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling.
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PMID:Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis. 1157 49

We have evaluated the in vivo correlation between the expression of cell cycle markers and skin tumor development in SKH-1 hairless mice in a complete photocarcinogenesis protocol. Irradiated mice developed an average of 16 tumors per animal by week 23 with the average number of carcinomas per mouse being 2.1. The expression of p53 and cyclins A and D1 was confined initially to sporadic single cells and gradually developed into foci of patchy intense staining in the basal and granular layers of UVB-exposed epidermis. p53 was expressed in all the papilloma sections examined, whereas cyclins D1 and A were expressed in 68 and 71% of these lesions, respectively. In UVB-induced squamous cell carcinomas (SCC), p53 was expressed in >90% of the tumors, whereas cyclin D1 was detected in 55% of the lesions, and cyclin A staining was limited to 27%. These immunohistochemical observations were confirmed by Western blotting and protein kinase assays. We observed an early wave of cyclin A overexpression and cyclin A protein kinase activity preceding the appearance of detectable tumors. Cyclin D1 and p53 overexpression were coupled with the development of tumors, and these changes are likely to be relevant to the pathogenesis of these lesions.
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PMID:Stage-specific alterations of cyclin expression during UVB-induced murine skin tumor development. 1183 28

Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Like squamous cell carcinomas, they are also believed to be ultraviolet (UV)-induced, but several data suggest that some differences might exist in the mechanisms of their UV induction. The originating cells may arise from interfollicular basal cells, hair follicles or sebaceous glands, thus from a deeper zone than the SCC ones, which probably means exposure to different doses or wavelengths of UV. The p53 gene and the patched gene (PTCH) are major targets of UV for BCC induction. Mutations in p53 are present in about 56% of human BCC, even small early lesions. The "UV signature" is observed in 65% of them. Mutations in the PTCH play also a major role in BCC development, being responsible for hereditary BCCs in Gorlin's syndrome, sporadic BCC, and BCCs isolated from xeroderma pigmentosum, although with a lower incidence of "UV signature". Smoothened-activating mutations and PTCH2 mutations are also involved in BCC formation. Transgenic mice overexpressing Smoothened or Sonic hedgehog in the skin spontaneously produce skin lesions resembling human BCCs, but contrary to findings in the hairless albino mouse and with SCC, no data on experimental UV induction of BCCs are available.
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PMID:Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms. 1196 27

The development of actinic keratosis (AK) and squamous cell carcinoma (SCC) is the result of a complex sequence of events initiated by exposure to ultraviolet (UV) light. The application of sunscreens prior to sun exposure has been reported to reduce the incidence of AK. The initial damage takes place in the DNA and most of the UV-induced lesions in the DNA are repaired. However, mutations may occur as a result of base mispairing of the cell and its DNA replicate before the DNA lesion is repaired. The genes involved in the repair process are also potential UV targets. Mutations in the tumour suppressor gene p53 are a common feature of AK and SCC. The hairless mouse is the best available animal model, in which lesions resembling human AK (papillomas), keratoacanthomas and SCCs may be induced. This model of multistage carcinogenesis offers an excellent tool for mechanistic studies. The relative efficacy of UV wavelengths (action spectrum) that induce SCC has been determined using the hairless mouse as a model. The action spectrum has been extrapolated to humans skin and is recognised worldwide.
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PMID:From actinic keratosis to squamous cell carcinoma. 1196 28

Solar ultraviolet (UV) radiation is a prominent environmental carcinogen, but it does not penetrate any deeper than the skin. The UV-related skin cancers are by far the most common form of cancer among white Caucasians in the USA and Australia, and this poses a serious public health problem. Chronic UV exposure of hairless mice is a well established model for squamous cell carcinomas in man. It is important to identify the essential physical variables, and explore fully how photocarcinogenesis evolves in dependence of these variables. The 3 main physical variables in photocarcinogenesis are (i) the wavelength of the radiation, (ii) the exposure and (iii) time. A good quantitative description of tumor induction and precursing stages can be given in terms of these variables. An analysis of this description shows us that the early induction of clusters of epidermal cells that over-express mutant p53 ('p53 patches') are closely and, most likely, causally linked to the eventual tumors. These p53 patches may thus serve as early indicators of tumor risk. The induction of an immune-tolerance toward the UV-induced tumors precedes the actual occurrence of the tumors at high daily doses, but extrapolation indicates that this order of events may be reversed at low daily doses. This disparity between the dose-time relationships for the tumor tolerance and the tumors needs to be investigated further. It could imply a shift to non-immunogenic tumors at low daily doses.
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PMID:Physical variables in experimental photocarcinogenesis and quantitative relationships between stages of tumor development. 1204 15

The increase of cell proliferation during early wound healing is thought to be regulated by a decrease of apoptosis. In contrast, the reduction of cellularity during final wound maturation may be controlled by an increase of apoptotic cell death. Herein we studied whether p53 is involved in wound healing-associated apoptosis and whether transient inhibition of p53 is effective to improve the early healing process of cutaneous wounds. Using intravital microscopic and immunohistochemical techniques in hairless mice, we demonstrated that in vivo inhibition of p53 by pifithrin-alpha (PFT-alpha; 2.2 mg/kg ip) accelerates early epithelialization and neovascularization of cutaneous wounds by (i) promoting leukocyte recruitment, (ii) increasing cell proliferation, and (iii) reducing apoptotic cell death. We further show that final wound closure with down-regulation of cell proliferation is not inhibited by PFT-alpha treatment, indicating that transient blockade of p53 function does not affect the process of wound maturation. Western blot analysis revealed that PFT-alpha lowered nuclear but not cytoplasmic p53, implying that cytoplasmic retention of p53 mediates the antiapoptotic effects of PFT-alpha. Furthermore, PFT-alpha significantly increased expression of proliferating cell nuclear antigen protein in whole extracts of cutaneous tissue and caused a rise in proliferation of wild-type, but not mutant, p53-expressing keratinocytes. From our study we conclude that transient inhibition of p53 supports the early cell proliferation required for rapid tissue repair and that this may represent an attractive approach in the treatment of delayed wound healing.
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PMID:Acceleration of cutaneous wound healing by transient p53 inhibition. 1217 45

Glycolic acid, an alpha-hydroxy acid derived from fruit and milk sugars, has been commonly used as a cosmetic ingredient since it was known to have photo-protective and anti-inflammatory effects, and anti-oxidant effect in UV-irradiated skin. However, little has been known about the functional role of glycolic acid on UV-induced skin tumorigenesis. We previously found that glycolic acid inhibited UV-induced skin tumor development in hairless mouse. In this study we investigated anti-tumor promoting mechanism of glycolic acid on the UV-induced skin tumor development. The ability of glycolic acid to inhibit the UVB-induced cytotoxicity, apoptosis and expression of apoptosis-regulatory genes (p53 and p21) was examined. We also investigated whether glycolic acid could inhibit UVB-induced alternation of cell cycle, c-fos expression and activation of transcription factor AP-1 in cultured immortalized human keratinocyte HaCaT cells. Glycolic acid treatment attenuated the UVB-induced cell cytotoxicity as well as apoptosis. Glycolic acid also inhibited the UVB-induced expression of c-fos and the activation of transcription factor AP-1, and inhibited mRNA levels of apoptosis-regulatory gene (p53 and p21). These results suggest that glycolic acid may exert the inhibitory effect on the UVB-induced skin tumor development by blocking the UVB-induced of apoptosis and cytotoxicity through inhibition of c-fos expression and activation of AP-1 in addition to the inhibition of p53-p2l response pathway.
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PMID:Inhibitory effect of glycolic acid on ultraviolet B-induced c-fos expression, AP-1 activation and p53-p21 response in a human keratinocyte cell line. 1221 82

Although epidemiologic evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung, and bladder cancers, no animal model for arsenic carcinogenesis has been successful. This lack has hindered mechanistic studies of arsenic carcinogenesis. Previously, we and others found that low concentrations (< or =5 microm) of arsenite (the likely environmental carcinogen), which are not mutagenic, can enhance the mutagenicity of other agents, including ultraviolet radiation (UVR) and alkylating agents. This enhancing effect appears to result from inhibition of DNA repair by arsenite, but not via inhibition of DNA repair enzymes. Rather, low concentrations of arsenite disrupt p53 function and upregulate cyclin D1. Failure to find an animal model for arsenic carcinogenesis might be because arsenite is not a carcinogen per se but acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR in hairless but immunocompetent Skh1 mice. Mice were given 10 mg/L sodium arsenite in drinking water (or not) and irradiated with 1.7 KJ/m(2) solar UVR 3 times weekly. As expected, no tumors appeared in any organs in control mice or in mice given arsenite alone. After 26 weeks irradiated mice given arsenite had a 2.4-fold increase in skin tumor yield compared with mice given UVR alone. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite were much larger and more invasive. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. Skin cancers in populations drinking water containing arsenic may be caused by the enhancement by arsenic compounds of carcinogenesis induced by UVR (or other environmental agents). It is possible that lung and bladder cancers associated with arsenic in drinking water may also require a carcinogenic partner.
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PMID:Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies. 1242 25

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.
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PMID:p53 mutations as a marker of skin cancer risk: comparison of UVA and UVB effects. 1244 58


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