Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we analyzed 10 human squamous cell carcinomas (SCCs) for alterations in the p53 tumor suppressor gene in exons 4 through 9 by single-strand conformation polymorphism (SSCP) analysis. We found that 2 of 10 SCCs displayed unusual SSCP alleles at exon 7 of the p53 gene. Subsequent cloning and sequencing of PCR-amplified exon 7 DNA from these two tumors revealed that one had a G----A transition at the first position of codon 244, predicting a glycine-to-serine amino acid change, while the other tumor exhibited a G----T base change at the second nucleotide of codon 248, predicting an arginine-to-leucine substitution. Because the mutations in the p53 tumor suppressor gene in both tumors were located opposite potential pyrimidine dimer sites (C-C), it is consistent with these mutations having been induced by the ultraviolet radiation present in sunlight. These studies demonstrate that inactivation of the p53 tumor suppressor gene, as well as activation of ras oncogenes, may be involved in the pathogenesis of some human skin cancers.
Mol Carcinog 1991
PMID:Mutations in the p53 tumor suppressor gene in human cutaneous squamous cell carcinomas. 179 82

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.
Mol Carcinog 1991
PMID:Ras gene mutation and amplification in human nonmelanoma skin cancers. 206 25

Melanins, pigments of photoprotection and camouflage, are very photoreactive and can both absorb and emit active oxygen species. Nevertheless, black skinned individuals rarely develop skin cancer and melanin is assumed to act as a solar screen. Since DNA is the target for solar carcinogenesis, the effect of melanin on Ultraviolet (UV)-induced thymine lesions was examined in mouse melanoma and carcinoma cells that varied in melanin content. Cells prelabeled with 14C-dThd were irradiated with UVC; DNA was isolated, purified, degraded to bases by acid hydrolysis and analyzed by HPLC. Thymine dimers were detected in all of the extracts of irradiated cells. Melanotic and hypomelanotic but not mammary carcinoma cell DNA from irradiated cells contained hydrophilic thymine derivatives. The quantity of these damaged bases was a function of both the UVC dose and the cellular melanin content. One such derivative was identified by gas chromatography-mass spectroscopy as thymine glycol. The other appears to be derived from thymine glycol by further oxidation during acid hydrolysis of the DNA. The finding of oxidative DNA damage in melanin-containing cells suggests that melanin may be implicated in the etiology of caucasian skin cancer, particularly melanoma. Furthermore, the projected decrease in stratospheric ozone could impact in an unanticipated deleterious manner on dark-skinned individuals.
Environ Mol Mutagen 1990
PMID:Melanin photosensitizes ultraviolet light (UVC) DNA damage in pigmented cells. 237 74

Previous studies have shown that c-Ha-ras-1 and other genes located on the short arm of chromosome 11 are frequently lost in a number of human tumors. We investigated whether similar losses of the c-Ha-ras-1 allele occurred in human squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). DNAs were isolated from 35 pairs of skin tumors (25 BCCs and 10 SCCs) and matching normal skin from the same patients and analyzed for c-Ha-ras gene polymorphism by Southern blot hybridization. Sixteen BCC patients and 1 SCC patient were constitutionally heterozygous for the c-Ha-ras gene in their normal skin DNA. Of these 17 patients, five patients (four with BCC and one with SCC) (29%) showed loss of one of the c-Ha-ras alleles in their tumor DNA. One of the constitutionally heterozygous BCC patients exhibited deletion of the 6.6-kb c-Ha-ras allele and an extra copy of the 7.8-kb allele. In summary, loss of heterozygosity at the c-Ha-ras locus occurred frequently (29%) in the 17 human skin cancers studied. However, our finding that 90% of the patients with SCC, as opposed to 36% of the patients with BCC, had only one of the c-Ha-ras alleles in their normal skin tissue requires further study. Whether c-Ha-ras homozygosity has any bearing on genetic susceptibility to SCC remains to be established.
Mol Carcinog 1989
PMID:Deletion of the c-Ha-ras-1 allele in human skin cancers. 269 Aug 53

Keratinocytes from mouse skin were cultured for a short period in vitro following single or multiple treatments at low dose levels in vivo with the known chromosome-damaging agent triethylenemelamine (TEM). The chemical was applied to the skin of HRA/Skh hairless mice at concentrations corresponding to those reported to initiate cancer in initiation-promotion assays. A significant dose-related depression in keratinocyte cell recovery occurred over the dose range 0.3-1 mg TEM/mouse (single or multiple treatments). Under the same conditions, a dose-related induction of micronuclei was observed using the cytokinesis-block method with cytochalasin B. A similar frequency of micronuclei was detected in binucleate cells from mice treated with single or multiple applications of TEM. Mice held for 12-48 h post-treatment, before removal of skin for in vitro culture, yielded highest micronuclei frequencies. These results indicate that the same target cell population, skin keratinocytes, can be used to investigate both genotoxicity and carcinogenesis, and that micronucleus induction in these cells may be a sensitive signal of skin cancer initiation.
Environ Mol Mutagen 1989
PMID:Initiating carcinogen, triethylenemelamine, induces micronuclei in skin target cells. 275 23

Mutations induced by UVB (313-nm) radiation, a wavelength in the region of peak effectiveness for sunlight-induced skin cancer in humans, have been analyzed at the sequence level in simian cells by using a plasmid shuttle vector (pZ189). We find that significant differences exist between the types of mutations induced by this solar wavelength and those induced by nonsolar UVC (254-nm) radiation. Compared with 254-nm radiation, 313-nm radiation induces more deletions and insertions in the region sequenced. In addition, although the types of base substitutions induced by the two wavelengths are broadly similar (in both cases, the majority of changes occur at G-C base pairs and the G-C to A-T transition is predominant), an analysis of the distribution of these base changes within the supF gene following irradiation at 313 nm reveals additional hot spots for mutation not seen after irradiation at 254 nm. These hot spots are shown to arise predominantly at sites of mutations involving multiple base changes, a class of mutations which arises more frequently at the longer solar wavelength. Lastly, we observed that most of the sites at which mutational hot spots arise after both UVC and UVB irradiation of the shuttle vector are also sites at which mutations arise spontaneously. Thus, a common mechanism may be involved in determining the site specificity of mutations, in which the DNA structure may be a more important determinant than the positions of DNA photoproducts.
Mol Cell Biol 1988 Dec
PMID:Determination of the spectrum of mutations induced by defined-wavelength solar UVB (313-nm) radiation in mammalian cells by use of a shuttle vector. 307 80

The generation of free oxygen radicals is believed to play an important pathogenic role in the development of various disorders. More than other tissues, the skin is exposed to numerous environmental chemical and physical agents such as ultraviolet light causing oxidative stress. In the skin this results in several short- and long-term adverse effects such as erythema, edema, skin thickening, wrinkling, and an increased incidence of skin cancer or precursor lesions. However, accelerated cutaneous aging under the influence of ultraviolet light, usually termed photoaging, is only one of the harmful effects of continual oxygen radical production in the skin. Others include cutaneous inflammation, autoimmunological processes, keratinization disturbances, and vasculitis. Vitamin E is the major naturally occurring lipid-soluble non-enzymatic antioxidant protecting skin from the adverse effects of oxidative stress including photoaging. Its chemistry and its physiological function as a major antioxidative and anti-inflammatory agent, in particular with respect to its photoprotective, antiphotoaging properties, are described by summarizing animal studies, in vivo tests on human skin and biochemical in vitro investigations. The possible therapeutic use in different cutaneous disorders, and pharmacological and toxicological aspects are discussed. Many studies document that vitamin E occupies a central position as a highly efficient antioxidant, thereby providing possibilities to decrease the frequency and severity of pathological events in the skin. For this purpose increased efforts in developing appropriate systemic and local pharmacological preparations of vitamin E are required.
J Mol Med (Berl) 1995 Jan
PMID:The role of vitamin E in normal and damaged skin. 763 44

Individuals affected by the autosomal recessive disease xeroderma pigmentosum (XP) are acutely sensitive to sunlight and predisposed to skin cancer on exposed areas. Cells cultured from XP patients are both UV sensitive and defective in the nucleotide excision repair of damaged DNA. These cellular phenotypes are amenable to experimental strategies employing complementation, an approach previously used to demonstrate the correction of XP-D phenotypes following the introduction of the XPD (ERCC2) gene. In the present study, we have characterized the genomic organization of the XPD (ERCC2) gene and found it to be comprised of 23 exons. These data were helpful in evaluating the functional integrity of alleles in two XP-D cell lines. In cell line GM436 a C-->G transversion was found at nucleotide position 1411 in the XPD (ERCC2) cDNA, a change expected to result in a Leu461Val substitution. Cell line XP67MA carries a C-->T transition in genomic DNA at nucleotide position 2176 in exon 22, introducing the termination codon TAG at amino acid 726. The latter would be expected to produce a protein truncated by 34 amino acids. Although expression of the normal XPD cDNA could be shown to correct the UV sensitivity phenotype in XP-D cells, cDNA constructs bearing either of the two mutations failed to yield complementation. These results confirm the role of ERCC2 in XP-D and illustrate the power of utilizing cellular phenotypes to evaluate the significance of single nucleotide substitutions.
Hum Mol Genet 1994 Oct
PMID:Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. 784 2

Mutations in the p53 tumor suppressor gene are detected in approximately half of non-melanoma skin cancers. The type of base-pair changes observed strongly suggests solar radiation as the causative mutagen. Mutations are distributed nonrandomly and form moderate hotspots. We studied the capacity of ultraviolet B light (UVB, 280-320 nm) to induce base-pair changes into the p53 exon 7 sequence extending from nt 14067 to 14075 in human skin fibroblasts. This sequence contains hotspot codon 248. UVB induced mostly C-->A and G-->T transversions. The base-pair change with the highest relative abundance was C-->A in the first position of codon 250 (CCC-->ACC), followed by (in diminishing relative abundance) G-->T in the third position of codon 249 (AGG-->AGT), C-->A in the first position of codon 248 (CGG-->AGG), and C-->A in the third position of codon 247 (AAC-->AAA). The C-->T transition in the third position of codon 247 (AAC-->AAT) occurred with moderate efficiency. These base-pair changes are compatible with pyrimidine photodimers as premutagenic lesions, but they could also form opposite 8-hydroxyguanine, which is the major oxidation product of guanine. No evidence was obtained for the presence of tandem double CC-->TT transitions in the untranscribed strand at codons 247/248 and 250. The relative abundance of mutations induced by UVB in the p53 sequence extending from codon 247 to 250 in human fibroblasts does not correlate with mutations observed in the DNA from non-melanoma skin cancer. This lack of correlation suggests that the mutability of this p53 sequence at the DNA level plays only a minor role in the pathogenesis of non-melanoma skin cancer in humans.
Mol Carcinog 1994 Aug
PMID:Ultraviolet B light-induced mutagenesis of p53 hotspot codons 248 and 249 in human skin fibroblasts. 806 78

We examined the expression of two groups of matrix metalloproteinases (MMPs), stromelysin and interstitial collagenase, in human skin cancer by northern blot analysis and in situ hybridization. Stromelysin-3 (ST-3) mRNA was overexpressed more than tenfold in 17 of 19 (89%) specimens of basal cell carcinoma (BCC) but in only three of 13 (23%) cutaneous squamous cell carcinomas (SCCs). Stromelysin-1 and -2 (ST-1/2) mRNA was overexpressed in three of 19 (16%) BCC and three of 13 (23%) SCC. Collagenase mRNA was overexpressed in nine of 19 (47%) BCC and three of 13 (23%) SCC. No mRNA for ST-3, ST-1/2, or collagenase was detected by northern analysis in 21 specimens of adjacent normal skin. Because of these findings, we examined the specific location of the ST-3 mRNA in BCC specimens by in situ hybridization. ST-3 mRNA was particularly abundant in the characteristic stroma adjacent to the invasive basaloid tumor islands of the BCC and absent in the malignant cells. Moreover, ST-3 mRNA was expressed and induced by phorbol ester treatment in adult dermal fibroblasts but not in keratinocytes. In vitro studies have shown that MMPs are involved in the degradation of extracellular matrix molecules. Our finding of ST-3 mRNA overexpression in 17 of 19 (89%) BCC specimens is consistent with a role for this molecule in local invasion of stroma by BCC. Our in situ hybridization data suggested that while ST-3 is not expressed by malignant basal cells themselves, these tumor cells may induce the expression of ST-3 in adjacent nonmalignant stromal elements such as fibroblasts.
Mol Carcinog 1994 Jan
PMID:Increased expression of stromelysin-3 in basal cell carcinomas. 829 80


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