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)

Photochemotherapy with 8-methoxypsoralen and long wavelength ultraviolet radiation (PUVA) is commonly used to treat psoriasis and vitiligo. These vastly different diseases respond to the therapy by different mechanisms even though the immediate effects of the therapy - photoadduct formation - is the same for both. Because psoriasis is not cured by PUVA, patients receive many treatments over their lifetime and develop a significant risk for the development of skin cancers (primarily squamous cell carcinomas). In this review the basic aspects of psoralen photobiology are reviewed briefly. In addition the impact of the analysis of mutations in the tumor suppressor gene, p53, are summarized. An unexpected mutation spectrum (very few T-->A transversions and frequent UVB signature C-->T transitions) suggest that effects other than direct DNA photoadduct formation may be at play. The roles of reactive oxygen species-induced base changes as well as other clastogenic factors are discussed. This analysis suggests that it may be possible to improve the therapeutic efficacy of PUVA by a careful evaluation of the mode of delivery.
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PMID:Psoriasis, PUVA, and skin cancer--molecular epidemiology: the curious question of T-->A transversions. 1053 1

Although the aetiology of the hypopigmentary disorder vitiligo is ill understood, it is clear that pigment producing cells are absent from vitiliginous lesional skin. The present study was designed to investigate the possible role of melanocyte-expressed apoptosis regulatory molecules in melanocyte disappearance. Flow cytometric evaluation of p53, p21, Bcl-2 and Bax revealed no differences in in vitro expression levels between normal control and non-lesional melanocytes. Moreover, no in situ immunohistological differences were observed in melanocytes present in control, non-lesional and perilesional skin. However, an enhanced number of p53+ nuclei, in the absence of detectable p21 expression, was detected in involved areas. The observed p53 expression pattern did not involve melanocytes and could be the result of ultraviolet (UV) A irradiation. Further, we showed that UVB is capable of modulating melanocyte-expressed apoptosis regulatory molecules. Consequently, a lethal dose of UVB was given to two groups of cultured normal control and non-lesional melanocytes. No significant differences were found when comparing the percentages and kinetics of UVB-induced apoptosis in these groups. In conclusion, our results indicate that the relative apoptosis susceptibility of melanocytes in vitiligo is comparable with that of normal control cells. It is therefore unlikely that vitiligo is causally related to dysregulation of apoptosis regulatory molecules.
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PMID:Expression and modulation of apoptosis regulatory molecules in human melanocytes: significance in vitiligo. 1097 31

Photochemotherapy with methoxsalen (8-methoxypsoralen) and long wavelength ultraviolet (UV) radiation (referred to as 'PUVA' for psoralen plus UVA) is commonly used to treat psoriasis and vitiligo. These vastly different diseases respond to the therapy by different mechanisms even though the immediate effects of the therapy--the photomodification of cellular biomolecules--is the same for each. Because psoriasis is not cured by PUVA, patients receive many treatments over their lifetime and have a significantly increased risk for the development of skin cancers (primarily squamous cell carcinomas). In this article the basic aspects of psoralen photobiology are reviewed briefly. Several recent studies describing the incidence of skin cancer in UVA treated psoriasis cohorts are comparatively reviewed. In addition the impact of the analysis of mutations in the tumor suppressor gene, p53, are summarized. An unexpected mutation spectrum (very few PUVA type T-->A transversions and frequent UVB solar signature C-->T transitions) suggest that effects other than direct DNA photoadduct formation may be at play. These analyses suggest that it may be possible to improve the therapeutic efficacy of PUVA by a careful evaluation of the mode of delivery. In this review the science behind PUVA is summarized. In addition, the incidence of skin cancer as a long term consequence of repeated treatments is surveyed. To relate clinical observations to molecular events, the nature of p53 mutations found in skin cancers from psoriasis patients is also analyzed. Finally some suggestions for improving the delivery of PUVA therapy are presented.
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PMID:The role of PUVA in the treatment of psoriasis. Photobiology issues related to skin cancer incidence. 1170 10

The human epidermis with an area of 1.8 m(2) is the outer most layer of the human body. Hence, this organ plays a pivotal role in the defence against reactive oxygen species (ROS) generated by UV or X-ray exposure, heat and other sources. Consequently, a plethora of defence mechanisms exist controlling the redox status in this compartment. The role of thioredoxin reductase (TR), thioredoxin (T) in antioxidant defence has gained widespread recognition. In the past it has been shown that thioredoxin protects against UVB-induced skin injury, as well as against peroxidative damage. Under normal conditions, TR reduces oxidised thioredoxin in the presence of NADPH. Reduced thioredoxin serves as an electron donor for thioredoxin peroxidase (TPx) which consequently reduces H(2)O(2) to H(2)O. In this context, it has been demonstrated that membrane associated TR correlates with different skin photo types I-VI (Fitzpatrick classification), where darker skin has significantly higher enzyme activity compared to very fair skin, underlining the importance of this system in ROS defence. Moreover, it was only recently demonstrated in vivo with non-invasive Fourier-Transform Raman spectroscopy that UVB generates H(2)O(2) in the epidermis in a dose-dependent manner. H(2)O(2) can oxidise the selenocysteine residue in the penultimate position of the carboxyl terminus of TR with a K(m) of 2.5 mM. This oxidation is followed by an upregulation of mRNA expression of the enzyme. Hence, it can be concluded that UVB generated H(2)O(2) induces TR. However, permanent H(2)O(2) levels induce the tumour suppressor p53 which in turn downregulates cytosolic TR. Therefore TR activities are under fine control by H(2)O(2). This conclusion is also supported by the observation that thioredoxin, the substrate for TR, migrates from the cytosol to the nucleus after UVB exposure. A new function for the TR/T/TPx system in epidermal cells has been discovered in the control of the important cofactor (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH(4)) homeostasis. Full oxidation of 6BH(4) to 6 biopterin via H(2)O(2) can lead to a cytotoxic environment for epidermal melanocytes. This cascade of events is observed in the depigmentation disorder vitiligo, where millimolar levels of H(2)O(2) can accumulate in the epidermis of affected individuals, consequently leading to cellular vacuolation in this compartment.
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PMID:Thioredoxin reductase - its role in epidermal redox status. 1174 5

Despite the lack of protective melanin and increased oxidative stress due to mM concentrations of epidermal H2O2 in vitiligo, there is no significantly increased risk for chronic actinic damage and non-melanoma skin cancer. Therefore the question arises, which protective mechanisms could be involved in the skin of these patients preventing the initiation of these cancers. Recently an overexpression of p53 has been shown in vitiligo. Unfortunately there was no further characterization of this elevated p53. Employing a functional colour yeast assay, the study presented herein demonstrates for the first time the overexpression of a functioning wild-type p53 protein in both depigmented and 'normal' pigmented epidermis of patients with vitiligo compared with healthy controls. Surprisingly long-term narrowband UVB (311 nm) treatment does not alter this expression. Moreover, MDM-2, PCNA and p21 protein expression remain unchanged compared with healthy controls. This increased epidermal p53 in vitiligo coincides with decreased thioredoxin reductase (TR) protein levels in both depigmented and pigmented skin whereas mRNA expression is unaffected. Because TR is one transcriptional target of p53, these results support a wild-type functionality, which was further supported by the specific p53 FASAY yeast test. To our knowledge this is the first example of persistent elevated functioning wild-type p53 in humans. Based on our results we hypothesize that the low incidence for actinic damage, basal cell and squamous cell carcinoma as documented in vitiligo could well reside in a protective function of up-regulated wild-type p53.
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PMID:Increased epidermal functioning wild-type p53 expression in vitiligo. 1282 40

Vitiligo depigmentation is considered a consequence of either melanocyte disappearance or loss of functioning melanocytes in the involved areas. However, it has been reported that keratinocytes in involved vitiligo skin are damaged too. Based on this evidence, we evaluated the in vitro behaviour, in life span cultures, of involved and uninvolved vitiligo keratinocytes and their expression of proliferation, differentiation and senescence markers. An additional purpose was to investigate whether vitiligo keratinocytes from depigmented skin are able to sustain survival and growth of normal melanocytes (when added in co-culture experiments), as normal human keratinocytes manage to do. Our results demonstrate that almost all involved vitiligo keratinocytes have a shorter life span in vitro than the uninvolved cells and all of them do not maintain melanocytes in culture in a physiological ratio. Modification of proliferation and senescence marker expression also occurs. Indeed, we detected low initial expression levels of the senescence marker p16 in involved vitiligo keratinocytes, despite their shorter in vitro life span, and increased expression of proliferating cell nuclear antigen and p53. This preliminary analysis of a small number of in vitro cultured vitiligo keratinocytes suggests an impaired senescence process in lesional vitiligo keratinocytes and attempts to regulate it.
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PMID:Keratinocyte cultures from involved skin in vitiligo patients show an impaired in vitro behaviour. 1763 Sep 62

Vitiligo is characterized by a patchy loss of inherited skin color affecting approximately 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H(2)O(2))-induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun-induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8-oxoguanine in the skin and plasma in association with epidermal up-regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76(MDM2). Short-patch base-excision repair via hOgg1, APE1, and polymerasebeta DNA repair is up-regulated. Overexpression of Bcl-2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO(-)) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO(-) (300 x 10(-6) M) abrogates DNA binding, while H(2)O(2)-oxidized p53 (10(-3) M) enhances DNA binding capacity and prevents ONOO(-)-induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we propose up-regulated wild-type p53 together with p76(MDM2) as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.
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PMID:Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage. 1964 Nov 44

Oxidative stress has been suggested as the initial pathogenetic event in melanocyte degeneration in vitiligo. Our previous results indicate that keratinocytes from perilesional skin show the features of damaged cells. In the present study, biopsies were taken from the perilesional skin of 12 patients suffering from nonsegmental vitiligo. The intracellular pathways involved in keratinocyte damage and apoptosis and the antioxidant protection of curcumin and capsaicin in these cells were investigated. In keratinocytes from perilesional vitiligo skin, we observed high levels of activated p38, NF-kB p65 subunit, p53, and Smac/DIABLO proteins. In contrast, low levels of ERK phosphorylation were present. To investigate the relationship between these pathways, we used specific inhibitors and evaluated the alteration of each pathway. For the first time, our study demonstrates the pivotal role of p38 MAP kinase as an upstream signal of perilesional keratinocyte damage, and the important contribution of p38 and NF-kB on p53 accumulation. Curcumin and capsaicin also increase ERK phosphorylation, thus inhibiting apoptosis. Moreover, pretreatment with such natural antioxidants inhibited caspase activation, increased total antioxidant capacity, repressed intracellular ROS generation and lipid peroxidation, and improved mitochondrial activity. These results suggest that antioxidants might represent an alternative approach to protect against vitiligo progression.
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PMID:The involvement of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: Protective effects of curcumin and capsaicin. 2008 92

Vitiligo occurs in Northern Europe in one of 200 people. The disease can cause significant psychological stress for the affected individual. These patients generate and accumulate massive amounts of H(2)O(2)- and peroxynitrite in the epidermal compartment. Consequently many proteins are oxidized or nitrated, leading in turn to partial or complete loss of functionality. Moreover, presence of DNA damage in the skin as well as in plasma has been shown, while apoptosis is not enhanced. Induction of DNA repair is associated with up-regulated functioning p53 protein. Considering possible genetic predisposition and /or spontaneous mutations, autoimmune reactions in the disease are put forward in the context of oxidative stress. In addition a review of recent and novel treatment modalities including the role of oxidative stress reduction and combined climatotherapy at the Dead Sea in a group are discussed.
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PMID:[Vitiligo. What is new?]. 2054 79

Vitiligo is characterized by the progressive disappearance of pigment cells from skin and hair follicle. Several in vitro and in vivo studies show evidence of an altered redox status, suggesting that loss of cellular redox equilibrium might be the pathogenic mechanism in vitiligo. However, despite the numerous data supporting a pathogenic role of oxidative stress, there is still no consensus explanation underlying the oxidative stress-driven disappear of melanocytes from the epidermis. In this study, in vitro characterization of melanocytes cultures from non-lesional vitiligo skin revealed at the cellular level aberrant function of signal transduction pathways common with neurodegenerative diseases including modification of lipid metabolism, hyperactivation of mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB), constitutive p53-dependent stress signal transduction cascades, and enhanced sensibility to pro-apoptotic stimuli. Notably, these long-term effects of subcytotoxic oxidative stress are also biomarkers of pre-senescent cellular phenotype. Consistent with this, vitiligo cells showed a significant increase in p16 that did not correlate with the chronological age of the donor. Moreover, vitiligo melanocytes produced many biologically active proteins among the senescence-associated secretory phenotype (SAPS), such as interleukin-6 (IL-6), matrix metallo proteinase-3 (MMP3), cyclooxygenase-2 (Cox-2), insulin-like growth factor-binding protein-3 and 7 (IGFBP3, IGFBP7). Together, these data argue for a complicated pathophysiologic puzzle underlying melanocytes degeneration resembling, from the biological point of view, neurodegenerative diseases. Our results suggest new possible targets for intervention that in combination with current therapies could correct melanocytes intrinsic defects.
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PMID:Vitiligo: a possible model of degenerative diseases. 2355 79


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