Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a case of lipodystrophia centrifugalis abdominalis infantilis (LCAI) showing apoptosis during the lipoatrophic process by immunohistochemical staining. A 3-year-old boy was seen with a 3-month history of a centrifugally spreading depressed eruption without pain and pruritus on his abdomen. He had fever, diarrhea and vomiting for a week at the beginning of his eruption. Physical examination revealed a palm-sized well-demarcated atrophic plaque on his lower abdomen and left inguinal fold. His plaque showed fine erythema peripherally. A skin biopsy specimen showed remarkably decreased subcutaneous fatty tissue. Inflammatory cell infiltration including lymphocytes and histiocytes was noted in the degenerating fatty tissue. In the degenerating subcutaneous fatty tissue, positive staining for HLA-DR, Fas, bcl-2, p53 and transferase-mediated uridine nick end labeling in mononuclear cells were observed. He was diagnosed as having LCAI. The present case showed the possible involvement of apoptosis in the fatty tissue degeneration in LCAI.
 ...
PMID:Lipodystrophia centrifugalis abdominalis infantilis-- immunohistochemical demonstration of an apoptotic process in the degenerating fatty tissue. 1114 55

Sunburn cell (SBC) formation in the epidermis is a characteristic consequence of ultraviolet radiation (UVR) exposure at doses around or above the minimum erythema dose. SBC have been identified morphologically and biologically as keratinocytes undergoing apoptosis. There is evidence that SBC formation is a protective mechanism to eliminate cells at risk of malignant transformation. The level of DNA photodamage is a major determinant of SBC induction by a process controlled by the tumor suppressor gene p53. However, extra-nuclear events also contribute to SBC formation, such as the activation of death receptors including CD95/Fas. UVR triggers death receptors either by direct activation of these surface molecules or by inducing the release of their ligands such as CD95 ligand or tumor necrosis factor. Oxidative stress also appears to be involved, probably via mitochondrial pathways, resulting in the release of cytochrome C. Pathways which modify SBC formation are now extensively studied given the importance of apoptosis in eliminating irreparably damaged cells. A greater understanding of the mechanisms that induce and prevent UVR-induced apoptosis will contribute to our understanding of mechanisms relevant in genomic integrity.
 ...
PMID:The molecular determinants of sunburn cell formation. 1138 Jun 10

Repeated skin exposure to ultraviolet radiation leads to increased tolerance for erythema. Whether this tolerance is accompanied by a significant protection against epidermal DNA injury has never been thoroughly investigated. In a first set of experiments we irradiated 25 healthy volunteers three times a week for 3 wk using solar-simulating tanning lamps. In addition, all individuals were exposed to a (challenge) dose of three times the initial minimal erythema dose on a small area of skin before the first and after the final exposure. On both occasions, cyclobutane pyrimidine dimers were quantified in biopsies. As expected, repeated ultraviolet exposures resulted in increased epidermal pigmentation and thickness. The ultraviolet sensitivity for erythema decreased on average by 75%. The cyclobutane pyrimidine dimer formation was reduced on average by 60%. In a second set of experiments, with a group of 13 subjects, DNA repair kinetics were assessed. Within a period of 5 d after a single, slightly erythemal dose (1.2 minimal erythema dose), levels of cyclobutane pyrimidine dimer and p53-expressing cells were determined in skin biopsies. Both markers of DNA damage were elevated upon the single ultraviolet exposure and returned to background levels after 3-4 d. This information is important when trying to minimize the risk of DNA damage accumulation after repeated exposures during a tanning course.
 ...
PMID:Solar-simulated skin adaptation and its effect on subsequent UV-induced epidermal DNA damage. 1156 76

Ultraviolet radiation of mouse skin leads to epidermal hyperplasia, inflammation, and subsequent tumor development. In this study we determined to what extent the cell cycle machinery is altered during epidermal proliferation after ultraviolet B radiation. A minimal erythema dose, 90 mJ per cm2, increased the protein expression of the G1 phase cyclins, cyclin D1 and E, by 12 h. The majority of epidermal cells entered S phase between 18 and 24 h as determined by 5'-bromo-2'-deoxyuridine incorporation, proliferating cell nuclear antigen, and cyclin A immunohistochemistry. An increase in cyclin-dependent kinase 2 (cdk-2) protein expression occurred after 12 h, but no changes in cdk-4 or cdk-6 protein levels were observed. The increase in cyclin D1, E, and A protein expression was associated with an increase in cyclin D1-cdk-4, cyclin E-cdk-2, and cyclin A-cdk-2 complex formation. p53 protein expression was elevated through 48 h, and the cdk inhibitor protein p21(Cip1/WAF1) was elevated 6-fold to 7.5-fold between 12 and 24 h. The elevated p21(Cip1/WAF1) protein contributed to an enhanced association with cdk-2 and cdk-4 at 3-24 h and 6-24 h post-ultraviolet B irradiation, respectively. These data indicate that 90 mJ per cm2 of ultraviolet B irradiation induces a DNA damage response, by increasing p53 and p21(Cip1/WAF1) protein expression, but also induces a rapid and sustained increase in S phase by 18 h.
 ...
PMID:Ultraviolet-B irradiation alters the cell cycle machinery in murine epidermis in vivo. 1171 Sep 29

As DNA damage induced by ultraviolet radiation plays an essential role in skin cancer induction, we pursued the measure of several DNA lesions induced by ultraviolet radiation in human skin for determining the efficacy of different topical photoprotectors. Non-exposed skin (buttocks from 20 individuals) was exposed to 10 doses of ultraviolet, which corresponded to three to four minimal erythema doses of solar-simulating radiation, and biopsies were taken at 24 h within the half and one minimal erythema dose sites and a nonirradiated, adjacent control area. We report that even suberythemal doses of ultraviolet radiation are capable of inducing substantial DNA damage, namely pyrimidine dimers, p53 induction, and the DNA base-modified product generated by oxidative stress, 8-hydroxy-2'-deoxyguanosine. All three lesions are induced in a dose-dependent manner. An additional eight individuals were treated with either ultraviolet B or ultraviolet B + ultraviolet A sunblock (sun protection factor 15) and exposed to 71/2 and 15 times the minimal erythema dose on each individual, with biopsies taken at 24 h post-ultraviolet. Pyrimidine dimer and p53 expression were rarely seen in nonirradiated skin but occasional staining was seen in all normal skin for 8-hydroxy-2'-deoxyguanosine. Applications of sunscreens to human skin before irradiation were shown to attenuate erythema but did not completely eliminate all three types of cellular damage when tested up to their sun protection factor 15. Furthermore, ultraviolet B + ultraviolet A sunscreens were less efficient than the ultraviolet B alone formulation for protection against all three lesions. These results suggest that DNA damage assessed in vivo by immunohistochemistry provides a very sensitive endpoint for determining the efficacy or photosensitivity of possible different protective measures in human skin.
 ...
PMID:Protection against pyrimidine dimers, p53, and 8-hydroxy-2'-deoxyguanosine expression in ultraviolet-irradiated human skin by sunscreens: difference between UVB + UVA and UVB alone sunscreens. 1188 5

Both in vivo skin immune responses and the skin's reaction to sun exposure integrate a complex interplay of biologic responses. The complexity and multiplicity of events that occur in the skin during an immune response make it a sensitive indication of both UVB and UVA-induced changes in the skin by sun damage, as well as those changes that are prevented by various sunscreens. Sunscreens are the most effective and widely available intervention for sun damage, other than sun avoidance or clothing. However, sunscreens vary widely in their relative ability to screen various UV waveband components, and their testing has been variably applied to outcomes other than for erythema to determine the sunburn protection factor (SPF), a measure primarily of UVB filtration only. Determination of an immune protection factor (IPF) has been proposed as an alternative or adjunctive measure to SPF, and recent studies show IPF can indeed detect added in vivo functionality of sunscreens, such as high levels of UVA protection, that SPF cannot. Clarification of the definition of IPF, however, is required. Excellent data are available on quantification of the IPF for restoring the afferent or induction arm of contact sensitivity, but other immune parameters have also been measured. Proposed here is nomenclature for whether the IPF is measured using contact sensitivity induction (IPF-CS-I), contact sensitivity elicitation (IPF-CS-E), delayed-type hypersensitivity elicitation (IPF-DTH-E), antigen-presenting cell function (IPF-APC-FXN) or numbers (IPF-APC-#), and cytokine modification such as IL-10 (i.e. IPF-cyto-IL-10). Similar nomenclatures could be used for other measures of skin function protection (i.e. DNA damage, p53 induction, oxidation products, etc.). A review of in vivo human studies, in which sunscreens are used to intervene in a UV-induced modulation of immune response, cells or cytokines, highlights the technical variables and statistical approaches which must also be standardized in the context of an IPF for regulatory or product claim purposes. Development of such IPF standards would allow the integration of both UVB and nonUVB (UVA, blue and possible IR) solar waveband effect-reversals, could be applied to integrate effects of other ingredients with protective function (i.e. antioxidants, retinoids, or other novel products), and would spur development of more advanced and complete protection products.
 ...
PMID:Protection against UV-induced suppression of contact hypersensitivity responses by sunscreens in humans. 1244 55

Epidermal keratinocytes undergo a process of terminal differentiation or cornification that in many aspects resembles apoptosis. It is characterized by the elimination of cell nuclei within the granular layer, whereas the cytoplasm is transformed into horn cells. Premature death of keratinocytes can be induced by extrinsic factors such as UV irradiation. We investigated the time-dependent expression of apoptotic marker proteins in the skin of one healthy human volunteer after irradiation with a fourfold minimal erythema dose (MED) of UVB. The data were supplemented by including healthy skin areas of biopsies from patients UVB-irradiated for therapeutic reasons. Punch biopsies were analysed by in situ end-labelling (ISEL) for DNA strand breaks and by immunohistochemistry for expression of p53, bcl-2, active caspase-3 and its proform, and deoxyribonuclease I (DNase I). Keratinocytes with pyknotic nuclei were first detected 6 h after UVB exposure, and apoptotic keratinocytes (sunburn cells) 12 h after exposure. These aggregated to sunburn bodies after 24 h. In control skin, nuclei with DNA strand breaks were only occasionally detected in the granular layer but 6 h after UVB irradiation in the spinous layer. After 12 h, many sunburn cells were ISEL-positive and positively stained for active caspase-3, P53, and DNase I. Morphometric evaluation of the immunohistochemical data demonstrated that maximal upregulation of P53, DNase I and activation of caspase-3 occurred 12 h after irradiation and in advance of the peak of apoptotic cell death reached after 24 h as verified by ISEL. In contrast, strong Bcl-2 immunostaining appeared restricted to presumed melanocytes and basal cells but was not increased after UVB irradiation.
 ...
PMID:Premature keratinocyte death and expression of marker proteins of apoptosis in human skin after UVB exposure. 1275 86

Since Fischer reported on the superiority of 313 nm UVB compared with broad band UVB in the treatment of psoriasis, narrow band UVB has become the main phototherapeutical modality in several countries. There is some discussion about the safety and photobiological effects of narrow band UVB. In the present study, narrow and broad band UVB have been compared with respect to parameters for photodamage and inflammation. Fourteen healthy volunteers were randomized in two groups. Both groups were irradiated with three minimal erythema doses (MED) of narrow or broad brand UVB, respectively. Before and 4, 24 and 48 h after irradiation, 6 mm biopsies were taken from immunohistochemical analysis of p53, apoptosis and p16 (photodamage parameters) and T-cells, polymorphonuclear leukocytes (PMN) and Langerhans' cells (inflammatory cells). Mean MED for narrow band UVB was 8.125 times higher than broad band UVB. Significant changes in expression were seen for all parameters except for p16. P53, apoptosis, T-cells and PMN increased, while Langerhans' cell count decreased significantly. No significant differences were seen between the narrow band UVB. In conclusion, following irradiation of three MED narrow band UVB and broad band UVB safety parameters for carcinogenesis and inflammation were induced to the same extent. As narrow band UVB is more effective than broad band UVB, the present study suggests superiority of narrow band UVB as a treatment with a better benefit risk ration.
 ...
PMID:The differential effect of broad band vs narrow band UVB with respect to photodamage and cutaneous inflammation. 1471 51

Sulindac is a nonsteroidal anti-inflammatory drug with demonstrated potency as a chemopreventive agent in animal models of carcinogenesis and in patients with familial adenomatous polyposis. Because tumor promotion is generally associated with exposure to pro-inflammatory stimuli, it is likely that anti-inflammatory agents may have potent antitumor effects. In human skin, sulindac reduces bradykinin-induced edema. In this study, we tested the hypothesis that the cyclooxygenase inhibitor sulindac can protect against ultraviolet (UVB)-induced injury that is crucial for the induction of cancer. Exposure of SKH-1 hairless mice to two consecutive doses of UVB (230 mJ/cm2) induces various inflammatory responses including erythema, edema, epidermal hyperplasia, infiltration of polymorphonuclear leukocytes, etc. Topical application of sulindac (1.25-5.0 mg/0.2 ml acetone) to the dorsal skin of SKH-1 hairless mice either 1 h before or immediately after UVB exposure substantially inhibited these inflammatory responses in a dose-dependent manner. Oral administration of sulindac in drinking water (160 ppm) for 15 days before and during UVB irradiation similarly reduced these inflammatory responses. These potent anti-inflammatory effects of sulindac suggested the possibility that the drug could inhibit signaling processes that relate to carcinogenic insult by UVB. Accordingly, studies were conducted to assess the efficacy of sulindac in attenuating the expression of UVB-induced early surrogate molecular markers of photodamage and carcinogenesis. UVB exposure enhanced the expression of p53, c-fos, cyclins D1 and A, and PCNA 24 h after irradiation. Treatment of animals with either topical or oral administration of sulindac largely abrogated the expression of these UVB-induced surrogate markers. These results indicate that the cyclooxygenase inhibitor sulindac is effective in reducing UVB-induced events relevant to carcinogenesis and that this category of topically applied or orally administered drugs may prove to be effective chemopreventive agents for reducing the risk of photocarcinogenesis in human populations.
 ...
PMID:Photoprotective effects of sulindac against ultraviolet B-induced phototoxicity in the skin of SKH-1 hairless mice. 1502 Feb

The transition from a normal cell to a neoplastic cell is a complex process and involves both genetic and epigenetic changes. The process of carcinogenesis begins when the DNA is damaged, which then leads to a cascade of events leading to the development of a tumor. Ultraviolet (UV) radiation causes DNA damage, inflammation, erythema, sunburn, immunosuppression, photoaging, gene mutations, and skin cancer. Upon DNA damage, the p53 tumor suppressor protein undergoes phosphorylation and translocation to the nucleus and aids in DNA repair or causes apoptosis. Excessive UV exposure overwhelms DNA repair mechanisms leading to induction of p53 mutations and loss of Fas-FasL interaction. Keratinocytes carrying p53 mutations acquire a growth advantage by virtue of their increased resistance to apoptosis. Thus, resistance to cell death is a key event in photocarcinogenesis and conversely, elimination of cells containing excessive UV-induced DNA damage is a key step in protecting against skin cancer development. Apoptosis-resistant keratinocytes undergo clonal expansion that eventually leads to formation of actinic keratoses and squamous cell carcinomas. In this article, we will review some of the cellular and molecular mechanisms involved in initiation and progression of UV-induced skin cancer.
 ...
PMID:Cellular and molecular events leading to the development of skin cancer. 1574 41


<< Previous 1 2 3 4 Next >>