Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The premutagenic oxidative DNA base damage, 7,8-dihydro-8-oxoguanine, is induced in human skin fibroblasts by monochromatic radiation ranging from a UVB wavelength (312 nm) up to wavelengths in the near visible (434 nm). The oxidative damage is not generated by absorption of radiation in DNA but rather by activation of photosensitizers generating genotoxic singlet oxygen species. The spectrum for the yield of the oxidative damage in confluent, non-growing, primary skin fibroblasts shows that it is UVA (above 334 nm) and near visible radiations which cause almost all of this guanine oxidation by natural sunlight in the fibroblast model. We estimate that the total amount of oxidation of guanine induced by sunlight in fibroblasts in the epidermis of the skin equals or exceeds the amount of the major type of direct DNA damage, cyclobutane pyrimidine dimers. In rapidly dividing lymphoblastoid cells, no oxidative guanine damage was induced. However, in melanoma cells almost as much damage as in non-growing fibroblasts (1.1 per 10(4) guanine bases after 1200 kJ/m2 UVA) was found. We conclude that oxidative DNA base damage can probably contribute to the induction of both non-melanoma and melanoma skin cancer by sunlight.
 ...
PMID:Induction of oxidative DNA base damage in human skin cells by UV and near visible radiation. 945 Apr 85

Thymidine kinase (TK) genes from three alpha-herpesviruses (i.e., human herpes simplex type 1, varicella-zoster virus, equid herpesvirus 4) and two y-herpesviruses (i.e., Epstein-Barr virus and Saimiri herpesvirus 2) were cloned in expression vectors based on zeocin resistance by complementation of a TK-defective Escherichia coli strain. In vivo complementation of an appropriate yeast strain and in vitro enzymatic measurements demonstrated that all viral TKs possess a second phosphorylating activity corresponding to the thymidylate kinase function in contrast to the E coli TK, which is deprived of this activity. When expressed in an engineered E coli strain rendered resistant to purine and pyrimidine nucleoside analogs, the viral TKs sensitize host bacteria to 3'-azido-3'-deoxythymidine (AZT), 3'-deoxy-2',3'-didehydrothymidine (D4T), dideoxyinosine, or fluorodeoxyuridine (5-FUdR). The extent of activation of all these analogs, in this bacterial assay, was found to be greatly superior for the two gamma-virus TKs, compared to the alpha-virus TKs, including the reference suicide gene, HSV1-TK. TK from the two gamma-Epstein-Barr and Saimiri 2 viruses were also found to be more efficient in sensitizing murine melanoma B16 tumor cells to pyrimide nucleoside analogs.
 ...
PMID:Phosphorylation and cytotoxicity of therapeutic nucleoside analogues: a comparison of alpha and gamma herpesvirus thymidine kinase suicide genes. 957 Feb 99

Although the induction of pigmentation following exposure of melanocytes to ultraviolet light in vivo and in vitro is well documented, the intracellular mechanisms involved in this response are not yet fully understood. Exposure to UV-B radiation leads to the production of DNA damage, mainly cyclobutane pyrimidine dimers, and it was recently suggested that the thymidine dinucleotide pTpT, mimicking small DNA fragments released in the course of excision repair mechanisms, could trigger melanin synthesis. We now report that the thymidine dinucleotide pTpT induces melanogenesis both in human normal adult melanocytes and in human melanoma cells. Thus, the SOS-like response suggested by Gilchrest's work to be evolutionary conserved, based primarily on work in murine cells and guinea pigs, is also apparently present in the human. Thymidine dinucleotide is nontoxic to melanoma cells and does not induce apoptosis in these cells, but induces S phase cell cycle arrest and a proliferation slow down. Because thymidine excess in culture medium leads to the synchronization of cells in S phase, we investigated whether this phenomenon was involved in the increase in melanin synthesis. We show that melanin synthesis is specifically triggered by the dimeric form of the thymidine and not by the monomeric form pT. Thus, our data strongly support that thymidine dinucleotides pTpT mimic at least part of the effects of ultraviolet irradiation, and may hence represent an invaluable model in the study of the molecular events involved in melanogenesis induction triggered through DNA damage.
 ...
PMID:Thymidine dinucleotides induce S phase cell cycle arrest in addition to increased melanogenesis in human melanocytes. 974 Feb 43

The tumor suppressor gene, CDKN2A (p16), encodes a cyclin-dependent kinase inhibitor and functions as a negative regulator in the retinoblastoma pathway that blocks cell cycle progression from the G1 phase. The gene has been found to be deleted, truncated, mutated, or silenced by promoter methylation in a wide range of tumor types. Where melanoma CDKN2A mutations have been characterized, C --> T and CC --> TT transitions were found, indicating a direct role for ultraviolet radiation (UVR)-induced pyrimidine dimers in the formation of some tumors. The South American opossum, Monodelphis domestica, has been shown by our group and others to be susceptible to the induction of melanoma on chronic exposure to UVR alone. The CDKN2A gene and its exon 1beta alternate transcript p19ARF were cloned and sequenced from M. domestica to investigate the role of these genes in the development of UVR-induced melanoma and non-melanoma tumors. Both genes were first amplified by polymerase chain reaction (PCR) using cDNA from an opossum corneal-tumor cell-line library and degenerate primers based on human, mouse, and rat CDKN2A gene sequences. To verify these as normal sequences, both genes were then RT-PCR amplified from cultured normal opossum melanocyte mRNA. When comparing the tumor and melanocyte sequences, we found a UVR signature point mutation, a C --> T transition, within exon 2 in the corneal tumor cell line. The same mutation at this site in other tumors has been shown to alter the CDKN2A protein's ability to bind CDK4 kinase, which may lead to uncontrolled cell cycling. A comparison of the amino acid sequence of opossum CDKN2A showed identities relative to human, mouse, and rat between 57% and 63%, and when conserved amino acid substitutions are considered (similarity), the range is 63% to 67%. The amino acid identity and similarity for p19ARF ranged from 39% to 49%.
 ...
PMID:Cloning and characterization of the CDKN2A and p19ARF genes from Monodelphis domestica. 983 7

The Ser122 --> Pro mutation in human nucleoside diphosphate kinase (NDK)-B/Nm23-H2 was recently found in melanoma cells. In comparison to the wild-type enzyme, steady state activity of NDKS122P with ATP and TDP as substrates was slowed down 5-fold. We have utilized transient kinetic techniques to analyze phosphoryl transfer between the mutant enzyme and various pairs of nucleoside triphosphates and nucleoside diphosphates. The two half-reactions of phosphorylation and dephosphorylation of the active site histidine residue (His118) were studied separately by making use of the intrinsic fluorescence changes which occur during these reactions. All apparent second order rate constants are drastically reduced, falling 5-fold for phosphorylation and 40-200-fold for dephosphorylation. Also, the reactivity of the mutant with pyrimidine nucleotides and deoxy nucleotides is more than 100-fold reduced compared with the wild-type. Thus, the rate-limiting step of the NDK-BS122P-catalyzed reaction is phosphoryl transfer from the phospho-enzyme intermediate to the nucleoside diphosphate and not phosphoryl transfer from the nucleoside triphosphate to the enzyme as was found for the wild-type protein. This results in a pronounced shift of the equilibrium between unphosphorylated and phosphorylated enzyme. Moreover, like the Killer-of-prune mutation in Drosophila NDK and the neuroblastoma Ser120 --> Gly mutation in human NDK-A/Nm23-H1, the Ser122 --> Pro substitution in NDK-B affects the stability of the protein toward heat and urea. These significantly altered properties may be relevant to the role of the mutant enzyme in various intracellular processes.
 ...
PMID:Human nucleoside diphosphate kinase B (Nm23-H2) from melanoma cells shows altered phosphoryl transfer activity due to the S122P mutation. 1040 Jun 30

It is well established, at least in mice, that not only ultraviolet C (UVC) or ultraviolet B (UVB), but also ultraviolet A (UVA) is able to induce squamous cell carcinomas. Results from animal models, epidemiological studies, and clinical observations suggest that UVA might play an important role in the pathogenesis of malignant melanoma as well. In contrast to UVC or UVB, UVA is hardly able to excite the DNA molecule directly and produces only few pyrimidine dimers. Oxidative DNA base damage, generated indirectly through photosensitizers, might be responsible for the mutagenic and carcinogenic properties of UVA. This is supported by differences in mutation spectra induced by UVA and UVB in mammalian cells and tumors. Avoidance of natural and artificial UVA sources is recommended, especially for melanoma-prone individuals.
 ...
PMID:Role of UVA in the pathogenesis of melanoma and non-melanoma skin cancer. A short review. 1059 68

Oral vitamin E (alpha-tocopherol) supplementation has been reported to improve facial hyperpigmentation. The compound of alpha-tocopherol and ferulic acid, also an antioxidant connected with an ester bond, alpha-tocopheryl ferulate (alpha-TF) can absorb ultraviolet (UV) radiation and thus maintain tocopherol in a stable state. Our aim was to determine whether alpha-TF can be applied to improve and prevent facial hyperpigmentation induced by UV as a whitening agent as well as an antioxidant. In this study, the effects of alpha-TF on melanogenesis were examined using cultured human melanoma cells and normal human melanocytes in vitro. alpha-TF solubilized in 0.5% lecithin inhibited melanization significantly at the concentration of 30 micrograms/ml compared with arbutin (100 micrograms/ml), kojic acid (100 micrograms/ml), ascorbic acid (600 micrograms/ml), and tranexamic acid (600 micrograms/ml). alpha-TF had no effect on the protein amounts of tyrosinase, TRP (tyrosinase related protein)-1, and TRP-2 of human melanoma cells exposed to UV radiation, but inhibited tyrosine hydroxylase activity. alpha-TF neither directly inhibited tyrosinase activity of the large granule fraction extracted from melanoma cells, nor modulated glycosylation of tyrosinase. These results suggest that alpha-TF may be a candidate for whitening agent which suppresses melanogenesis, possibly by inhibiting tyrosine hydroxylase activity in an indirect manner. Further, alpha-TF decreased the amount of 8-hydroxydeoxyguanosine produced indirectly through active oxygen species (AOS) in guinea pig skin exposed to 2 times the minimal erythema dose of UVB radiation, but did not suppress the direct formation of cyclobutane pyrimidine dimers and (6-4) photoproducts. Thus alpha-TF may reduce AOS-induced DNA damage and thereby contribute at least in part to suppressing or retarding skin cancer development.
 ...
PMID:The inhibitory effect of DL-alpha-tocopheryl ferulate in lecithin on melanogenesis. 1062 56

The DNA lesions induced by ultraviolet radiation include cyclobutane pyrimidine dimers and 6-4 photoproducts. We investigated whether cutaneous melanoma patients have an impaired ability to repair their ultraviolet-induced photolesions. Seventeen patients with melanoma and 13 healthy controls took part in this study. Both groups received a dose of 40 mJ per cm2 Commission Internationale de l'Eclairage of solar simulating radiation on previously unexposed buttock skin. Skin biopsies were taken at 0 h, 24 h, and 48 h after ultraviolet exposure. A 32P-postlabeling method was used to measure both cyclobutane pyrimidine dimers and 6-4 photoproducts in skin. Cyclobutane pyrimidine dimers and 6-4 photoproduct levels did not differ in the melanoma patients from those in the control group at any time point post-ultraviolet radiation. The repair rate of cyclobutane dimer TT=C was faster than that for TT=T both at 24 h and 48 h postirradiation in both groups, providing evidence of site-specific repair (p < 0.05). We conclude that patients with melanoma have a normal ultraviolet-induced DNA repair capacity in skin in situ.
 ...
PMID:Cutaneous melanoma patients have normal repair kinetics of ultraviolet-induced DNA repair in skin in situ. 1073 64

The gray, short-tailed opossum, Monodelphis domestica, has been used for photobiologic studies since 1984. The presence of a light-activated DNA repair pathway in the tissues of Monodelphis has been used to identify pyrimidine dimers in DNA as initiating events for a number of ultraviolet radiation (UVR)-induced pathologies of the skin and cornea. Furthermore, Monodelphis, unlike common laboratory rodents, is susceptible to the induction of melanoma by UVR alone.
 ...
PMID:Photobiology of Monodelphis domestica. 1078 75

The genus Xiphophorus is an important model for investigating the etiology and genetics of sunlight-induced melanoma as well as other cancers. We used immunological techniques to determine the induction, distribution and repair of cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone dimers ([6-4]PD) in different tissues of Xiphophorus signum exposed to ultraviolet-B light. We found that the (6-4)PD was induced at 5 to 10-fold lower frequency than the CPD and that scalation provided considerable photoprotection against both photoproducts. Photoenzymatic repair (PER) was very efficient in X. signum with most of the lesions removed within 20 min; PER of CPD occurred at about twice the rate of (6-4)PD. Nucleotide excision repair (NER) was much less efficient than PER and the rates of CPD and (6-4)PD removal were comparable. PER was more efficient in the caudal fin compared to the lateral epidermis; the opposite was true for NER. Although the initial rate of CPD excision was five-fold faster in the lateral epidermis compared to the caudal fin a considerable amount of residual damage remained in both tissues. The diverse photochemical and photobiological responses observed in X. signum suggest that heritable traits governing deoxyribonucleic acid damage induction and repair may be involved in the susceptibility of other Xiphophorus species to melanomagenesis.
 ...
PMID:Induction, distribution and repair of UV photodamage in the platyfish, Xiphophorus signum. 1094 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>