Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Xeroderma pigmentosum (XP) variant patients are genetically predisposed to sunlight-induced skin cancer. Fibroblasts derived from these patients are extremely sensitive to the mutagenic effect of UV radiation and are abnormally slow in replicating DNA containing UV-induced photoproducts. However, unlike cells from the majority of XP patients, XP variant cells have a normal or nearly normal rate of nucleotide excision repair of such damage. To determine whether their UV hypermutability reflected a slower rate of excision of photoproducts specifically during early S phase when the target gene for mutations, i.e., the hypoxanthine (guanine) phosphoribosyltransferase gene (HPRT), is replicated, we synchronized diploid populations of normal and XP variant fibroblasts, irradiated them in early S phase, and compared the rate of loss of cyclobutane pyrimidine dimers and 6-4 pyrimidine-pyrimidones from DNA during S phase. There was no difference. Both removed 94% of the 6-4 pyrimidine-pyrimidones within 8 h and 40% of the dimers within 11 h. There was also no difference between the two cell lines in the rate of repair during G1 phase. To determine whether the hypermutability resulted from abnormal error-prone replication of DNA containing photoproducts, we determined the spectra of mutations induced in the coding region of the HPRT gene of XP variant cells irradiated in early S and G1 phases and compared with those found in normal cells. The majority of the mutations in both types of cells were base substitutions, but the two types of cells differed significantly from each other in the kinds of substitutions, but the two types differed significantly from each other in the kinds of substitutions observed either in mutants from S phase (P < 0.01) or from G1 phase (P = 0.03). In the variant cells, the substitutions were mainly transversions (58% in S, 73% in G1). In the normal cells irradiated in S, the majority of the substitutions were G.C --> A.T, and most involved CC photoproducts in the transcribed strand. In the variant cells irradiated in S, substitutions involving cytosine in the transcribed strand were G.C --> T.A transversions exclusively. G.C --> A.T transitions made up a much smaller fraction of the substitutions than in normal cells (P < 0.02), and all of them involved photoproducts located in the nontranscribed strand. The data strongly suggest that XP variant cells are much less likely than normal cells to incorporate either dAMP or dGMP opposite the pyrimidines involved in photoproducts. This would account for their significantly higher frequency of mutants and might explain their abnormal delay in replicating a UV-damaged template.
Mol Cell Biol 1993 Jul
PMID:Evidence from mutation spectra that the UV hypermutability of xeroderma pigmentosum variant cells reflects abnormal, error-prone replication on a template containing photoproducts. 832 Dec 29

The gene encoding the tumour suppressor protein p53 is one of the most commonly mutated genes in human cancers. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure.
Mol Med Today 1996 Jan
PMID:The p53 tumour suppressor gene: a model for molecular epidemiology of human cancer. 879 49

Ultraviolet radiation (UVR) present in sunlight is a major environmental factor capable of affecting human health and well being. The organ primarily affected by UVR is the skin, which is composed of a variety of different cell types. Here, UVR is needed for production of active vitamin D as well as producing undesirable effects such as sunburn, premature cutaneous photoaging, and promoting skin cancer development. Depending on the radiation dose, UVR influences virtually every cutaneous cell type investigated differently. Since the end of the nineteenth century, sun exposure has been known to induce skin cancer, which is now the human malignancy with the most rapidly increasing incidence. In several experimental models, mid-range UVR has been demonstrated to be the major cause of UV-induced cutaneous tumors. The stratospheric ozone layer protecting the terrestrial surface from higher quantum energy solar radiation is being damaged by industrial activities resulting in the possibility of increased UVR exposure in the future. Investigations in the field of experimental dermatology have shown that within the skin an immunosurveillance system exists that may be able to detect incipient neoplasms and to elicit a host responses against it. This article reviews the literature on studies designed to investigate the effects of UVR on cutaneous cellular components, with special focus on the immune system within the skin and the development of UV-induced cancer.
Crit Rev Biochem Mol Biol 1996 Dec
PMID:UV-induced cutaneous photobiology. 899 3

Because most non-melanocytic human skin cancers have p53 mutations, it is unclear whether the aberrant growth of these cancers is simply a result of the abrogation of a p53 downstream mediator, the universal cyclin-dependent kinase inhibitor p21WAF1. To investigate the role of p21WAF1 in human skin carcinogenesis, we studied its regulation in normal and p53-mutated immortalized human keratinocytes. In proliferating human normal keratinocytes (HNK), more wild-type p53 protein (wt p53) was expressed than in growth-arrested differentiating keratinocytes. However, the function of wt p53 as a transcriptional activator of the p21WAF1 gene was suppressed in proliferating keratinocytes. In response to ultraviolet B irradiation, expression of wt p53 increased in proliferating keratinocytes, but p21WAF1 transcriptional activation was not induced. Two isoforms of mdm2 (p57 and p90), which can bind to wt p53 and negatively regulate wt p53 function, were expressed in proliferating HNK, suggesting that mdm2 may play a role in the suppression of wt p53's function in proliferating HNK. Increased expression of p21WAF1 was detected in both Ca(2+)-induced growth-arrested and differentiating HNK, in which the wt p53 expression was down regulated. This reflects the complexity of the p53/p21WAF1 pathways of cell-cycle regulation and differentiation in keratinocytes. No p21WAF1 expression was detected in human immortalized keratinocytes (HaCaT) or in two ras-transformed variants, HaCaT ras I/7 and HaCaT ras II/3, which have two p53 mutations. Retrovirus-mediated expression of p21WAF1 stopped the growth of all these cell types, but expression of wt p53 did not affect the cells' growth properties. p21WAF1 also downregulated human telomerase RNA component mRNA expression in HaCaT cells. This novel function of p21WAF1 partly explains the suppression of telomerase activity by p21WAF1 expression in HaCaT. Taken together, these results are consistent with the idea that p21WAF1 successfully inhibits the growth of non-melanocytic skin cancers, even those with alterations in p53, p21ras, retinoblastoma gene product, and telomerase activity.
Mol Carcinog 1998 Jan
PMID:Growth arrest of immortalized human keratinocytes and suppression of telomerase activity by p21WAF1 gene expression. 947 69

Xeroderma pigmentosum (XP) complementation group F was first reported in Japan and most XP-F patients reported to date are Japanese. The clinical features of XP-F patients are rather mild, including late onset of skin cancer. Recently a cDNA that corrects the repair deficiency of cultured XP-F cells was isolated. The XPF protein forms a tight complex with ERCC1 and this complex functions as a structure-specific endonuclease responsible for the 5' incision during DNA excision repair. Here we have identified XPF mRNA mutations and examined levels of the mRNA and protein expression in seven primary cell strains from Japanese XP-F patients. The XP-F cell strains were classified into three types in terms of the effect of the mutation on the predicted protein; (i) XPF proteins with amino acid substitutions; (ii) amino acid substituted and truncated XPF proteins; and (iii) truncated XPF protein only. A normal level of expression of XPF mRNA was observed in XP-F cells but XPF protein was extremely low. These results indicate that the detected mutations lead to unstable XPF protein, resulting in a decrease in formation of the ERCC1-XPF endonuclease complex. Slow excision repair of UV-induced DNA damage due to low residual endonuclease activity provides a plausible explanation for the typical mild phenotype of XP-F patients.
Hum Mol Genet 1998 Jun
PMID:Characterization of molecular defects in xeroderma pigmentosum group F in relation to its clinically mild symptoms. 958 Jun 60

The number and diversity of mutations in the p53 mutation data base provides indirect evidence that implicates environmental mutagens in human carcinogenesis. The p53 gene has a large mutational target size; more than 280 out of 393 amino acids are found mutated in tumors. We argue that there is possibly a limited involvement of selection for specific mutations in the central domain of the protein, and that the distribution of DNA damage along the p53 gene caused by environmental carcinogens can be correlated with the mutational spectra, i.e., hotspots and types of mutations, of certain cancers. This concept has been validated by experiments with sunlight and the cigarette smoke component benzo[a]pyrene representing the polycyclic aromatic hydrocarbon class of carcinogens. The damage/repair data obtained for these mutagens can predict certain parameters of the mutational spectra including the distribution of hotspots in human nonmelanoma skin cancers and lung cancers from smokers. Future studies with suspected mutagens may help to implicate causative agents involved in other cancers, such as colon and breast cancer, where the exact carcinogen has not yet been identified but an environmental factor is suspected.
Environ Mol Mutagen 1998
PMID:Formation and repair of DNA lesions in the p53 gene: relation to cancer mutations? 958 58

It is now recognized that ultraviolet (UV) radiation is a potent environmental insult capable of interfering with immunity to skin cancers and modifying certain immunologic reactions within both locally irradiated skin and distant, unexposed sites. Exposure to UVB light (290-320 nm) induces a potent cutaneous inflammatory response that involves the infiltration of leukocytes into the dermis as well as the production of proinflammatory cytokines by both resident epidermal keratinocytes and dermal cells. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been shown to be a major mediator of UVB light effects on cutaneous immunity. Recent studies have demonstrated that pentoxifylline (PTX), a xanthine-derived phosphodiesterase inhibitor, has the ability to inhibit synthesis of TNF-alpha. To examine the effects of PTX on UVB-mediated cutaneous inflammation, Skh/hr hairless mice were injected intraperitoneally with either phosphate-buffered saline or 50 microg/g PTX 1 h before exposure to 2240 J/m2 UVB. Reverse transcription-polymerase chain reaction and immunohistochemical techniques were used to demonstrate that 24 h to 1 wk after UVB-light irradiation, PTX inhibited UVB-induced TNF-alpha gene expression, inhibited the increase in epidermal TNF-alpha protein synthesis, blocked the increase in epidermal proliferation observed after exposure to UVB light, and decreased production of myeloperoxidase by neutrophils infiltrating into the dermis. These studies demonstrated that PTX modifies epidermal responses after acute UVB light exposure and suggest that PTX treatment may be used clinically to modulate the deleterious effects of long-term UVB-light irradiation.
Mol Carcinog 1998 May
PMID:Inhibitory effects of pentoxifylline on ultraviolet B light-induced cutaneous inflammation. 960 97

The Hedgehog family of secreted glycoproteins proteins plays multifarious roles during vertebrate embryogenesis. In both the Drosophila and vertebrate embryo correct deployment of Hedgehog-like proteins is critical for the generation of pattern in many tissues and organs. New evidence now reveals that genes involved in hedgehog signalling are mutated in a number of common human genetic disorders, including skin cancer and craniofacial defects. The understanding of how cells generate, receive and transduce the Hedgehog signal during development has led to the establishment of molecular paradigms for the pathogenesis of these diseases. These studies clearly illustrate that knowledge of the normal role of a gene during development is critical for generating an understanding of the disease state in which it is mutated.
J Mol Med (Berl) 1998 May
PMID:Hedgehog's escape from Pandora's box. 962 99

The mutational specificity of UV-light is characterized by an abundance of C to T transition mutations at dipyrimidines containing cytosine or 5-methylcytosine. A significant percentage of these mutations are CC to TT double transitions. Of the major types of UV-induced DNA lesions, the cis-syn cyclobutane pyrimidine dimers (CPDs) are thought to be the most mutagenic lesions, at least in mammalian cells. It has been proposed that the CPDs become mutagenic perhaps only after cytosine bases within these dimers deaminate to uracil and the resulting U-containing photolesions are correctly bypassed by DNA polymerases. In order to assess the significance of this proposed mutagenic mechanism, we have developed two methods to specifically measure deaminated CPDs in UV-irradiated human cells or DNA. The first method is based on enzymatic photoreversal of CPDs, followed by cleavage of the DNA with uracil DNA glycosylase, an AP lyase activity, and ligation-mediated PCR to map the resulting strand breaks. The second method, which can be used to detect double deamination events (CC to UU), is PCR amplification of photolyase-treated DNA using primers complemetary to the deaminated sequences. We have measured deamination events in the human p53 gene, which contains a large percentage of C to T transitions in skin cancers. The deamination reactions are specific for cytosine within CPDs, are negligible immediately after irradiation, and are time-dependent and DNA sequence context-dependent. Twenty four hours after irradiation of human fibroblasts with UVB light, between 10 and 60% of most CPD signals are converted to the deaminated form, depending on the sequence. Significant deamination occurs at skin cancer mutation sites in the p53 gene. Double deamination also occurs and this reaction can involve dimers containing 5-methylcytosine or cytosine. These double events are expected to occur more frequently in cells with a DNA repair defect because there is more time for deamination in unrepaired lesions. This may explain the relatively high frequency of CC to TT mutations in skin cancers from xeroderma pigmentosum patients. In summary, these novel detection techniques demonstrate that deamination of cytosine in pyrimidine dimers is a significant event that most likely contributes to the mutational specificity of UVB irradiation in human cells.
J Mol Biol 1998 Nov 27
PMID:Sequence and time-dependent deamination of cytosine bases in UVB-induced cyclobutane pyrimidine dimers in vivo. 981 19

To assess whether vertebrates can acquire, from their diet, ultraviolet radiation-absorbing mycosporine-like amino acids (MAAs), medaka fish and hairless mice were maintained for 150 and 130 days, respectively, on diets either including Mastocarpus stellatus (rich in MAAs) or the same diets without this red alga. In medaka, the MAAs palythine and asterina-330, present in trace quantities in the diet with added M. stellatus, were present in significantly greater quantities in the eyes of fish fed this diet than in the eyes of control fish. Only traces of MAAs were present in the skin of medaka fed the diet containing MAAs. Shinorine, the principal MAA in M. stellatus, was not found in any tissues of medaka, which raises questions about the specificity of transport of MAAs. In hairless mice, no dietary MAAs were found in the tissues of the eyes, skin, or liver after maintenance on the experimental diet. Low concentrations of shinorine were present only in the tissues of the small and large intestines. These results indicate that MAAs are acquired from their diet and translocated to superficial tissues by teleost fish, but that mammals may be incapable of such. Thus, dietary supplementation with MAAs may be useful in aquacultured species of fish, but MAAs as 'dietary sunscreens' may not be an option for mammals, including humans. Nevertheless, our demonstration of the uptake of shinorine by human skin cancer cells in culture raises evolutionary questions regarding the organ specificity of the capacity for the cellular transport of MAAs.
Comp Biochem Physiol A Mol Integr Physiol 1998 Aug
PMID:Ultraviolet radiation-absorbing mycosporine-like amino acids (MAAs) are acquired from their diet by medaka fish (Oryzias latipes) but not by SKH-1 hairless mice. 982 92


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