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)

Nordihydroguaiaretic acid (NDGA) is a polyphenolic compound from the Larrea tridentata bush that has been identified as a chemopreventive drug in animal studies. Topically applied NDGA has been shown to prevent phorbol ester promotion of tumors in mouse skin, suggesting that NDGA may be a candidate drug for the chemoprevention of skin cancer. Ultraviolet (UV) B irradiation from sunlight exposure is the major cause of human skin cancer. UVB irradiation causes epigenetic alterations in target keratinocytes, such as the upregulation of signal transduction pathways that induce the expression of transcription factors. Specifically, UVB induces activator protein-1 (AP-1), a transcription factor complex that alters normal cellular gene expression. A component of the UVB-induced AP-1 complex, c-fos, also was identified as a mediator of the signaling pathway that leads to AP-1 activation. Thus, NDGA was investigated as a potential inhibitory agent for UVB-induced signaling pathways in the human keratinocyte cell line HaCaT. NDGA significantly inhibited UVB-induced c-fos and AP-1 transactivation. In addition, NDGA was found to inhibit activity of phosphatidylinositol 3-kinase (PI 3-kinase), a UVB-inducible enzyme that contributes to the induced expression of c-fos and AP-1. Therefore, NDGA prevents UVB-induced c-fos expression and AP-1 transactivation by inhibiting the PI 3-kinase signaling pathway. Effective skin chemoprevention strategies may incorporate NDGA to inhibit components of the UVB-induced cell signaling pathways that increase AP-1 activity.
Mol Carcinog 2002 Jun
PMID:Nordihydroguaiaretic acid-mediated inhibition of ultraviolet B-induced activator protein-1 activation in human keratinocytes. 1211 16

Ultraviolet (UV) radiation is an environmental agent that has a major impact on humans, and cumulative exposure poses a serious risk in terms of developing skin cancer. Acute doses of UV induce apoptotic cell death in the skin via signalling pathways that are, in part, dependent on the p53 tumour suppressor protein. However, p53-independent mechanisms have also been described. Recent findings show that a high proportion of non-melanoma skin cancers contain human papillomavirus. The viral E6 protein effectively blocks the epidermal apoptotic response to UV and might play a key role in promoting tumour development in cooperation with the mutagenic effects of UV.
Trends Mol Med 2002 Sep
PMID:Papillomaviruses: death-defying acts in skin cancer. 1222 12

Merkel nerve endings are mechanoreceptors in the mammalian skin. They consist of large, pale cells with lobulated nuclei forming synapse-like contacts with enlarged terminal endings of myelinated nerve fibers. They were first described by F.S. Merkel in 1875. They are found in the skin and in those parts of the mucosa derived from the ectoderm. In mammals (apart from man), the largest accumulation of Merkel nerve endings is found in whiskers. In all vertebrates, Merkel nerve endings are located in the basal layer of the epidermis, apart from birds, where they are located in the dermis. Cytoskeletal filaments consisting of cytokeratins and osmiophilic granules containing a variety of neuropeptides are found in Merkel cells. In anseriform birds, groups of cells resembling Merkel cells, with discoid nerve terminals between cells, form Grandry corpuscles. There has been controversy over the origin of Merkel cells. Results from chick/quail chimeras show that, in birds, Merkel cells are a subpopulation of cells derived from the neural crest, which thus excludes their development from the epidermis. Most recently, also in mammals, conclusive evidence for a neural crest origin of Merkel cells has been obtained. Merkel cells and nerve terminals form mechanoreceptors. Calcium ions enter Merkel cells in response to mechanical stimuli, a process which triggers the release of calcium from intracellular stores resulting in exocytosis of neurotransmitter or neuromodulator. Recent results suggest that there may be glutamatergic transmission between Merkel cell and nerve terminal, which appears to be essential for the characteristic slowly adapting response of these receptors during maintained mechanical stimuli. Thus, we are convinced that Merkel cells with associated nerve terminals function as mechanoreceptor cells. Cells in the skin with a similar appearance as Merkel cells, but without contact to nerve terminals, are probably part of a diffuse neuroendocrine system and do not function as mechanoreceptors. Probably these cells, rather than those acting as mechanoreceptors, are the origin of a highly malignant skin cancer called Merkel cell carcinoma.
Anat Rec A Discov Mol Cell Evol Biol 2003 Mar
PMID:Friedrich Sigmund Merkel and his "Merkel cell", morphology, development, and physiology: review and new results. 1255 39

Telomerase, a ribonucleoprotein, is capable of adding telomeric sequences (TTAGGG hexameric repeats) to the ends of chromosomes and, thereby, halting the erosion of chromosome at each cell division. Whereas most normal somatic cells contain minimal or no detectable telomerase activity, most immortal and tumour cells exhibit significant levels of telomerase activity and show no net loss of telomere length during proliferation. The evaluation of telomerase has been proposed for diagnostic and therapeutic purposes in human cancer. Skin cancer is the most common cancer in humans; the precise molecular events in skin carcinogenesis are numerous and complicated and not yet completely clarified. In this study, we evaluated telomerase in 35 basal cell carcinomas and in 14 squamous cell carcinomas in order to determine if activation of the telomerase enzyme was a pivotal step in the development of skin cancer and whether telomerase activity levels were different between the two histotypes. A higher enzymatic level was shown to be associated with squamous cell carcinomas, while low levels were mainly detected in the basal cell histotype (chi2 test; p=0.02). Telomerase complex activity is dependent on its catalytic subunit, telomerase reverse transcriptase hTERT. By reverse transcription-PCR, using primers within the reverse transcriptase domain of hTERT, we observed a significant correlation between hTERT expression and telomerase activity in our skin tumour samples (p=0.0003). We detected the presence of multiple, alternately spliced transcripts, corresponding to full-length messages as well as spliced messages with critical reverse transcriptase motifs deleted. A higher telomerase messenger level was shown to be associated with squamous cell carcinomas (chi2 test; p<0.0001), as for telomerase activity. Our results provide arguments supporting the role of telomerase in skin cancer and suggest RT-PCR of telomerase RNA as a tool easier and faster than TRAP assay to identify more aggressive malignancies among non-melanoma skin specimens.
Int J Mol Med 2003 May
PMID:Evaluation of telomerase in non-melanoma skin cancer. 1268 97

We have demonstrated previously that suppression of some or all of the IFN-stimulated gene factor 3 (ISGF-3) proteins in skin squamous cell carcinomas is an early event in squamous skin carcinogenesis. This finding led to the hypothesis that suppressed expression of ISGF-3 proteins may lead to reduced IFN responsiveness, which in turn may contribute to skin malignancy by conferring a growth and/or survival advantage. To test this hypothesis, we have developed a skin cell-based model for inhibiting the IFN-alpha signaling pathway through the forced expression of a dominant negative-acting signal transducer and activator of transcription 2 (dnSTAT2) protein. Expression of dnSTAT2 suppressed cell growth inhibition with a pharmacologically achievable concentration (100 IU/ml) of IFN-alpha in the IFN-alpha-sensitive skin squamous cell carcinoma cell line SRB12-p9. dnSTAT2 also suppressed the IFN-alpha-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2, which are early events following IFN-alpha treatment, but did not suppress the IFN-gamma-induced phosphorylation of STAT1. Finally, the dnSTAT2 protein suppressed the up-regulation of several IFN-alpha-inducible genes that were identified in this system by cDNA microarray screening. We conclude that the cell growth-inhibitory effect of IFN-alpha in skin cells requires an intact STAT2 protein and is therefore mediated by the ISGF-3 complex. These results support STAT2 as an important molecular target for skin cancer chemoprevention. Furthermore, we propose that these dnSTAT2-expressing cells provide a novel in vitro model for the study of type I IFN action in human skin cells.
Mol Cancer Ther 2003 May
PMID:Dominant negative signal transducer and activator of transcription 2 (STAT2) protein: stable expression blocks interferon alpha action in skin squamous cell carcinoma cells. 1274 7

Xeroderma pigmentosum (XP) is a skin cancer-prone autosomal recessive disease characterized by inability to repair UV-induced DNA damage. The major form of XP is defective in nucleotide excision repair (NER) and comprises seven complementation groups (A-G). The genes defective in all groups have been identified unambiguously with the exception of group E. The cells of some XP-E patients are deficient in a protein complex (consisting of two subunits: p127/DDBI and p48/DDB2) which binds to UV-damaged DNA (UV-DDB) and is specifically involved in the removal of photoproducts from the non-transcribed regions of the genome. However, other XP-E patients have been reported not to lack UV-damaged DNA binding activity (DDB(+)). Here we describe several genetically unrelated XP-E patients, not previously analyzed in depth, each carrying two mutated alleles for DDB2, causing either a single amino acid change or a protein truncation or internal deletion. These defects result in a severe decrease of detectable p48 protein, abolish interaction with the p127 subunit, and produce a deficiency in UV-DDB binding activity (DDB(-)). The role of p48 in the repair defect of these patients was demonstrated in vivo and in vitro. Investigation of four DDB(+) cell strains from patients previously assigned to XP-E, allowed us to reclassify all of them into other groups and to show that they do not share the molecular and biochemical features typical for XP-E. Besides confirming that the true XP-E phenotype is DDB(-), resulting from defects in a single gene, DDB2, our results identify the functional domains of the corresponding p48 protein.
Hum Mol Genet 2003 Jul 01
PMID:True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product. 1281 79

Photodynamic therapy (PDT) is a therapeutic modality involving the use of a photosensitizing agent activated by light to destroy tumor cells. Over the past 25 years, PDT has been shown useful in the treatment of actinic keratoses and certain nonmelanoma skin cancers, such as Bowen's disease and basal cell carcinoma. We review the current data available for PDT with systemic photofrin and topical 5-aminolevulinic acid (ALA). PDT offers many advantages including its non-invasiveness and its ability to treat multiple lesions simultaneously and is, therefore, an interesting alternative for treating certain skin malignancies.
Mol Immunol 2003 Jul
PMID:Photodynamic therapy for nonmelanoma skin cancers. Current review and update. 1283 91

In mycosis fungoides (MF), T-cell clonality is reported in about 90% of skin and 40% of blood samples. However, identity of blood and cutaneous T-cell clone and prognostic relevance of blood T-cell clonality remain controversial. By PCR/fluorescence fragment analysis with estimation of clonal fragment lengths and relative peak heights, we objectively identified T-cell clonality unrelated to malignant lymphoproliferation in healthy donors (5/38), autoimmune dermatoses (3/8), and nonlymphoma skin cancer (9/39). This T-cell expansion of undetermined significance (TEXUS) was also found in 8/64 MF patients. Dissemination of neoplastic cells into blood, as identified by identical clonal fragment lengths in blood and skin, was detected in 23/64 MF patients. When monitoring for progression at TNM stage for a mean of 45.7 months, univariate analysis identified age of >60 years and detection of a related blood T-cell clone to be of prognostic relevance, whereas detection of TEXUS, sex, TNM stage at initial diagnosis, and detection of a cutaneous T-cell clone were irrelevant. Although multivariate analysis was not possible, further stratification clearly indicated an age of >60 years to be the predominating prognostic factor. In conclusion, investigation of T-cell clonality in skin and blood samples at the initial diagnosis cannot predict the clinical course of MF and the occurrence of TEXUS should be considered when assessing blood T-cell clonality.
Diagn Mol Pathol 2003 Sep
PMID:Peripheral blood T-cell clonality in mycosis fungoides and nonlymphoma controls. 1296 Jun 96

Inflammation, which includes the release of growth factors, proinflammatory cytokines and prostaglandins, the infiltration and activation of inflammatory cells, and the induction of oxidative DNA damage, is known to play a role in cancer development. The combination of damage to the skin resulting from chronic ultraviolet light B (UVB) exposure itself and the inflammatory response it induces is a major source of skin cancer development. Cyclooxygenase-2 (COX-2), an inflammatory enzyme responsible for the production of prostaglandins, is now implicated in the development of epithelial cancers, including squamous cell carcinoma in the skin. Previous work conducted in our laboratory has shown that topical treatment with celecoxib following UVB irradiation inhibits several parameters of acute inflammation, including vascular permeability, the infiltration and activation of neutrophils, and the production of prostaglandin E(2) (PGE(2)). The present studies expanded these observations, demonstrating the ability of topical celecoxib to inhibit acute oxidative damage. In addition, long-term studies illustrate the effectiveness of topical treatment with this drug in reducing chronic inflammation and UVB-induced papilloma/carcinoma formation. This data provides compelling evidence to explore the clinical efficacy of topically applied COX-2 inhibitors for the prevention of human skin cancers.
Mol Carcinog 2003 Oct
PMID:Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment. 1450 44

UVB radiation is a complete carcinogen able to initiate, promote, and progress keratinocyte cells toward carcinogenesis. Exposure to UVB leads to the propagation of a number of signal transduction pathways resulting in increased DNA binding of transcription factors, including activator protein-1 (AP-1), and subsequent gene expression. To test the hypothesis that AP-1 activation plays a role in the promotion of UVB-induced skin tumors, a dominant negative c-jun (TAM67) mutant transgene was expressed in the epidermis of SKH-1 hairless mice and bred with mice expressing an AP-1 luciferase reporter gene. Single UVB exposure experiments showed a significant decrease in AP-1 activity, as measured by luciferase levels, in mice expressing TAM67 72 h postexposure. Transgenic and nontransgenic littermates were placed into a chronic UVB exposure experiment, three exposures per week for 25 weeks. Expression of TAM67 reduced the number of tumors per mouse by 58% and tumor sizes were 79% smaller than the tumors present in the nontransgenic study group. These tumors were histologically identified as squamous cell carcinomas. TAM67 had no effect on UVB-induced hyperplasia because comparable epidermal thickening was observed in both study groups over a 5-day period post-UVB exposure. Immunohistochemical analysis showed a reduction in the number of cyclin D(1)-expressing cells in squamous cell carcinoma samples removed from the TAM67 study group. These data show that TAM67 can inhibit UVB-induced squamous cell carcinoma formation, suggesting that AP-1 is a good candidate target for the development of new chemoprevention strategies to prevent sunlight-induced skin cancers.
Mol Cancer Res 2003 Sep
PMID:Expression of dominant negative c-jun inhibits ultraviolet B-induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model. 1451 47


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