Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recessive autosomal hereditary disease, xeroderma pigmentosum (XP), is characterized by a high incidence of tumors in sun-exposed skin. The defect in early steps of excision repair of XP cells leads to hypermutability towards UV-mimicking agents. DNA from eight XP tumors were screened for activated transforming genes using 3T3 transfection. In two skin tumors isolated from a XP child, an activated N-ras oncogene was detected. Synthetic oligonucleotide probes were used to characterize the mutation in the ras gene. Both tumors were found to be mutated in the 61st N-ras codon from gln to his. The mutation was accompanied by an increase in the level of N-ras specific mRNA and in one transformant, by the alteration of the p21 protein. In the same tumors, c-myc amplification and over transcription, and Ha-ras gene rearrangement and amplification were also detected. Analysis of other XP tumors with eleven different oncogene probes revealed an amplification of the Ha-ras gene in 6 out of 10 cases. The normal skin fibroblasts from XP patients show normal pattern levels of N-ras, c-myc and Ha-ras sequences. The hypothesis is proposed that the presence of several oncogene alterations in the same tumor could be due to the high amount of UV-induced DNA lesions found in the exposed skin cells, in the absence of efficient repair.
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PMID:Activated oncogenes in human skin tumors from a repair-deficient syndrome, xeroderma pigmentosum. 264 47

The search for the genetic targets responsible for tumorigenesis has led to the identification of a number of cancer genes or cellular oncogenes (c-oncogenes). The oncogenes are activated forms of the proto-oncogenes, which are normal cellular genes and are scattered throughout the cellular genome. The number of known cellular proto-oncogenes and associated oncogenes now exceeds 30. There are different proto-oncogene families and their products have different functions and cellular localisation. They may function in normal cells in the process of proliferation, regulation of cellular metabolism through signal transfer, or cell differentiation. Activation of proto-oncogenes in man is now assumed to be due to: 1) point mutation; 2) overexpression or 3) gene rearrangement. The observation that in some tumors multiple oncogenes are altered could be interpreted in terms of a multigene hypothesis. However, in some cases, a single properly-activated oncogene may be able to trigger the whole process of malignant conversion. It is difficult to correlate, without ambiguity, tumor induction to specific types of DNA lesions in human tumors. Xeroderma pigmentosum (XP), a rare recessive autosomal skin disorder characterized biochemically as a DNA repair-deficient disease, is the first example in which unrepaired UV-induced DNA lesions are directly responsible for tumorigenesis. In two independent XP skin tumors, isolated from the same patient, we have detected several (N-ras, c-myc, Ha-ras) altered oncogenes in the same tumor. We postulate that the modifications we have found in these tumors are primarily due to the presence of unrepaired UV-adducts. Long term treatment of human tumoral cell lines bearing an activated ras oncogene, with Interferon-alpha (IFN), showed that IFN can affect the phenotype of the tumor cells without altering the expression of the activated ras gene. IFN may have the capacity to affect diverse cellular pathways. Consequently, the nature of the biological response of a given type of tumor cell to IFN may depend on its inherent properties.
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PMID:Activated oncogenes in human tumors. 268 33

The transcriptional level of c-myc, c-jun and XRCC1 genes after X-irradiation was compared in human cells originating from subjects presumably with different DNA repair abilities. The mRNA amount of the beta-actin gene was used as an internal standard of transcription. The relative mRNA level of c-myc and XRCC1 genes was significantly increased 15 min after X-irradiation with doses of 2-8 Gy in ataxia telangiectasia (AT) cells (AT5BIVA and TAT2SF), in contrast to little change in xeroderma pigmentosum (XP2OS(SV) and XP2YO(SV)) and normal cells (WI38VA13 and GM0637). The increased mRNA level of the XRCC1 gene in AT5BIVA and of the c-myc and XRCC1 genes in TAT2SF cells was maintained for up to 8 h after X-irradiation with 2 Gy. For the c-jun mRNA level after X-irradiation with 2-8 Gy, no significant change was observed in all cell lines tested. These results indicate that AT cells show a high transcriptional response of certain genes in response to X-irradiation, and suggest that the transcriptional activation of c-myc and XRCC1 genes after X-irradiation may be related to the hyper-radiosensitivity of AT cells.
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PMID:X-ray-induced transcriptional activation of c-myc and XRCC1 genes in ataxia telangiectasia cells. 751 22

In comparison with primary cell cultures, SV40-transformed human skin fibroblasts, either from healthy donors or from patients suffering from ataxia-telangiectasia (AT) or xeroderma pigmentosum, are more resistant to the cytotoxic action of low LET 60cobalt gamma-rays as well as to high LET alpha-particles. Resistance factors calculated from D10's lie between 1.4 and 2.0. Northern blot analysis reveals spontaneous overexpression of the oncogenes c-myc, Ki-ras and c-raf and of the tumour suppressor gene p53 as a consequence of SV40 transformation. For c-myc, the increased expression is due to gene amplification and gene rearrangement. An even further increase in the expression of c-myc has been found for AT cells (AT5BI-VA) after moderate doses of 60cobalt gamma-irradiation. A possible correlation between SV40-induced changes in gene expression and cellular radioresistance is discussed.
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PMID:Alterations in oncogene expression and radiosensitivity in the most frequently used SV40-transformed human skin fibroblasts. 791 16

We have examined the gene- and strand-specific DNA repair of UV-induced cyclobutane pyrimidine dimers in fibroblasts from normal individuals and from patients with the DNA repair-deficient disorder xeroderma pigmentosum (XP). Cells were studied from XP complementation groups A, C, D, and F. DNA repair was assessed in the essential, active gene, dihydrofolate reductase (DHFR), in the active c-myc protooncogene, and in the transcriptionally inactive delta-globin gene. In addition, repair was studied in the individual strands of the DHFR gene in normal and group C cells. In the two strains of group C cells, we find preferential DNA repair of the DHFR gene and a strand bias of the repair with more repair in the transcribed strand. This is in general accordance with previously published reports (Venema, J., van Hoffen, A., Natarajan, A.T., van Zeeland, A.A., and Mullenders, L.H.F. (1990) Nucleic Acids Res. 18, 443-448; Venema, J., van Hoffen, A., and Mullenders, L.H.F. (1991) Mol. Cell. Biol. 11, 4128-4134), but we now find that there is more repair in the nontranscribed strand and less in the transcribed strand than what has been observed previously. In XP group A and D strains, we find little or no gene-specific DNA repair. In cells from an individual in XP complementation group F, we find less repair of dimers in the active gene than what has been observed for the overall genome. We have also measured the colony-forming ability of the strains after treatment with UV and find that this measure of survival does not correlate with the level of gene-specific repair of dimers. Thus, XP group F represents a novel repair phenotype with little or no gene-specific repair of dimers, but with relatively high UV resistance. We also evaluate the XP patients' clinical features in relation to gene-specific repair of dimers.
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PMID:Gene-specific DNA repair in xeroderma pigmentosum complementation groups A, C, D, and F. Relation to cellular survival and clinical features. 844 62

Xeroderma pigmentosum (XP) patients are clinically characterized by a very high incidence of skin cancers on exposed skin, at an early age. XP cells in vitro are strongly deficient in excision-repair and highly mutagenized by UV light. We were, therefore, interested in measuring mutation frequency and in determining mutation spectra in patients' tumors exposed to UV lesions. We chose to look at oncogene activation in skin tumors with the idea that more mutations, particularly of the ras gene family, would be found in XP tumors where lesions remain unrepaired compared to normal individuals. Our results clearly show that more than a 2-fold significantly higher mutation frequency (50%) of the ras genes was found in XP in contrast to control tumors (22%). The majority of the mutations were found at codon 12 of all three ras genes with a preponderance for N-ras in XP samples. The mutation spectra indicate that all mutations found were located opposite pyrimidine-pyrimidine sequences which represent a hot spot for UV-induced DNA lesions. Most of the mutations were of the type expected from studies performed in vitro with model systems. This high mutation frequency in XP was accompanied by a very high level of Ha-ras and c-myc gene amplification and rearrangement. All these data are consistent with a fundamental role of unrepaired UV-induced DNA lesions as an initiating event in human skin tumors on exposed parts of the body.
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PMID:High mutation frequency in ras genes of skin tumors isolated from DNA repair deficient xeroderma pigmentosum patients. 845 33

Dermal fibroblast strains cultured from affected members of a cancer-prone family with Li-Fraumeni syndrome (LFS) harbor a point mutation in one allele of the p53 tumor suppressor gene, resulting in loss of normal p53 function. In this study we have examined the ability of these p53-deficient strains to carry out the long-patch mode of excision repair, mediated by DNA polymerases delta and epsilon, after exposure to 60Co gamma radiation or far ultraviolet (UV) (chiefly 254 nm) light. Repair was monitored by incubation of the irradiated cultures in the presence of aphidicolin (apc) or 1-beta-D-arabinofuranosylcytosine (araC), each a specific inhibitor of long-patch repair, followed by measurement of drug-induced DNA strand breaks (reflecting non-ligated strand incision events) by alkaline sucrose velocity sedimentation. The LFS strains displayed deficient repair capacity in response to both gamma rays and UV light. The repair anomaly in UV-irradiated LFS cultures was manifested not only in the overall genome, but also in the transcriptionally active, preferentially repaired c-myc gene. Using autoradiography we also assessed unscheduled DNA synthesis (UDS) after UV irradiation and found this conventional measure of repair replication to be deficient in LFS strains. Moreover, both apc and araC decreased the level of UV-induced UDS by approximately 75% in normal cells, but each had only a marginal effect on LFS cells. We further demonstrated that the LFS strains are impaired in the recovery of both RNA and replicative DNA syntheses after UV treatment, two molecular anomalies of the DNA repair deficiency disorders xeroderma pigmentosum and Cockayne's syndrome. Together these results imply a critical role for wild-type p53 protein in DNA polymerase delta/epsilon-mediated excision repair, both the mechanism operating on the entire genome and that acting on expressed genes.
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PMID:Faulty DNA polymerase delta/epsilon-mediated excision repair in response to gamma radiation or ultraviolet light in p53-deficient fibroblast strains from affected members of a cancer-prone family with Li-Fraumeni syndrome. 862 79

Inherited mutations of the TFIIH helicase subunits xeroderma pigmentosum (XP) B or XPD yield overlapping DNA repair and transcription syndromes. The high risk of cancer in these patients is not fully explained by the repair defect. The transcription defect is subtle and has proven more difficult to evaluate. Here, XPB and XPD mutations are shown to block transcription activation by the FUSE Binding Protein (FBP), a regulator of c-myc expression, and repression by the FBP Interacting Repressor (FIR). Through TFIIH, FBP facilitates transcription until promoter escape, whereas after initiation, FIR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regulation by FBP and FIR affect proper regulation of c-myc expression and have implications in the development of malignancy.
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PMID:Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. 1123 93

Altered gene expression of the DNA repair- and cell proliferation-associated proteins/enzymes was examined during the process of tamoxifen-induced hepatocarcinogenesis in female Sprague-Dawley rats. When rats were treated by gavage with a single dose of tamoxifen (20 mg/kg body weight) or with the same dose given at 24-h intervals for 2, 12 or 52 weeks, no histopathological change was observed in the liver after 2 weeks. Pathologically altered cell foci and placental form of glutathione-S-transferase (GST-P)-positive foci were observed in the liver after 12 weeks of treatment. Treatment for 52 weeks resulted in the formation of liver hyperplastic nodules that strongly expressed GST-P. During the process of carcinogenesis, changes in hepatic gene expression of DNA repair proteins/enzymes (XPA and XPC, xeroderma pigmentosum complementation groups A and C, respectively; APE, apurinic/apyrimidinic endonuclease) and of cell proliferation-associated proteins (c-myc; PCNA, proliferating cell nuclear antigen; cyclin D1, cyclin B, and p34cdc2) were examined by RT-PCR. The gene expression of XPA and APE was increased by the tamoxifen treatment for 2 or 12 weeks, but no increase was observed after the 52-week treatment. In addition, no significant change in XPC gene expression occurred at any period examined. The gene expression of c-myc, PCNA, and cyclin D1 was increased in a time-dependent fashion up to 12 weeks of treatment, and this increase was maintained up to 52 weeks of treatment. The gene expression of cyclin B and p34cdc2 was increased after the 1-day treatment, reverted to the control level at 2 and 12 weeks of treatment, and was remarkably increased after the 52-week treatment. In the present study, we demonstrate the altered gene expression of various proteins/enzymes involved in DNA repair, cell growth and the cell cycle during the process of tamoxifen-induced hepatocarcinogenesis. We discuss the relationship between the altered gene expression and hepatocarcinogenesis.
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PMID:The gene expression of hepatic proteins responsible for DNA repair and cell proliferation in tamoxifen-induced hepatocarcinogenesis. 1284 65

A continuous stream of activating and repressing signals is processed by the transcription complex paused at the promoter of the c-myc proto-oncogene. The general transcription factor IIH (TFIIH) is held at promoters prior to promoter escape and so is well situated to channel the input of activators and repressors to modulate c-myc expression. We have compared cells expressing only a mutated p89 (xeroderma pigmentosum complementation group B [XPB]), the largest TFIIH subunit, with the same cells functionally complemented with the wild-type protein (XPB/wt-p89). Here, we show structural, compositional, and functional differences in transcription complexes between XPB and XPB/wt-89 cells at the native c-myc promoter. Remarkably, although the mean levels of c-Myc are only modestly elevated in XPB compared to those in XPB/wt-p89 cells, the range of expression and the cell-to-cell variation of c-Myc are markedly increased. Our modeling indicates that the data can be explained if TFIIH integrates inputs from multiple signals, regulating transcription at multiple kinetically equivalent steps between initiation and promoter escape. This helps to suppress the intrinsic noise of transcription and to ensure the steady transcriptional output of c-myc necessary for cellular homeostasis.
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PMID:TFIIH operates through an expanded proximal promoter to fine-tune c-myc expression. 1560 38


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