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)

We demonstrated previously that the nucleoside of fludarabine (F-ara-A), a clinically effective agent against chronic lymphocytic leukemia and low-grade lymphoma, produces synergistic cytotoxicity against cisplatin-resistant CP2.0 human colon tumor cells when administered in combination with cisplatin. The purpose of this study was 2-fold: (i) to determine whether the synergy occurs in K562 human chronic myelogenous leukemia cells, which, unlike CP2.0 cells, are relatively resistant to drug-induced apoptosis because they express P210(bcr-abl) and (ii) to study the underlying mechanism for the synergy if the enhancement of cytotoxicity occurs in K562 cells. When K562 cells were treated with fludarabine nucleoside and cisplatin as single agents for 4 hr, IC50 values for fludarabine and cisplatin were 3.33 and 2.28 microM, respectively, as measured by a clonogenic survival assay. The simultaneous treatment of K562 cells with the two agents resulted in synergistic cell killing as determined by median-effect analysis. Such synergistic cell killing by combined cisplatin and fludarabine could not be detected in repair-deficient human xeroderma pigmentosum cell lines. Within the range of cytotoxic concentrations, fludarabine (2.5-15 microM) and cisplatin (3-30 microM) as single agents produced no detectable internucleosomal DNA fragmentation as revealed by gel electrophoresis, nor did the combination of the two drugs induce apoptotic DNA degradation. The effects of fludarabine on the repair of cisplatin-induced DNA adducts and interstrand cross-links in K562 cells were analyzed to determine their correlation with the cytotoxic synergy. The interstrand cross-links were measured by the ethidium bromide binding fluorescence assay and quantitative Southern blotting technique. Repair of the intrastrand adducts was detected with whole-cell extracts using a cisplatin-damaged plasmid as the substrate for the in vitro repair assay. Fludarabine at clinically achievable concentrations (1.5-4.5 microM fludarabine nucleoside; 20-100 microM fludarabine triphosphate) inhibited the repair of the DNA lesions induced by cisplatin in a dose-dependent fashion in K562 cells but not in xeroderma pigmentosum cells. Cotreatment with fludarabine preferentially increased the number of interstrand cross-links induced by cisplatin in actively transcribed genes in K562 cells. These data demonstrate the DNA-repair-inhibitory effect of fludarabine and suggest that this effect may contribute to the synergistic cytotoxicity of the fludarabine/cisplatin combination that resulted in decreased clonogenic survival of apoptosis-resistant K562 cells.
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PMID:Fludarabine-mediated repair inhibition of cisplatin-induced DNA lesions in human chronic myelogenous leukemia-blast crisis K562 cells: induction of synergistic cytotoxicity independent of reversal of apoptosis resistance. 935 70

The BCR gene is involved in the formation of the BCR-ABL oncogene responsible for the pathogenesis of Philadelphia chromosome-positive human leukemias. We have previously shown that P210 BCR-ABL binds to the xeroderma pigmentosum group B protein (XPB) through the portion of BCR that is homologous to the catalytic domain of GDP-GTP exchangers such as yeast CDC24 and Dbl. In the baculovirus overexpression system which facilitates binding of coexpressed proteins, we now show that XPB binds to the intact BCR protein efficiently but not to CDC24 or Dbl, suggesting specificity of this interaction. The binding of endogenous BCR and XPB proteins was also detected in Hela cells, and this was inhibited by a blocking peptide. Full-length (1-782) XPB and its truncated form (203-782), which does not contain the nuclear localization signal, were tagged with glutathione S-transferase (GST) and were expressed in Rat1 fibroblasts. GST-XPB(203-782) was localized predominantly in the cytoplasm and bound to BCR but not to p62, one of the other components in TFIIH. GST-XPB(1-782) was largely in the nucleus and bound to p62 and BCR. Although the biological significance of the binding remains to be uncovered, BCR binds to the XPB/p62 complex.
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PMID:BCR binds to the xeroderma pigmentosum group B protein. 1040 66

This paper commemorates the multiple contributions of Dirk Bootsma to human genetics. During a scientific 'Bootsma' cruise on his sailing-boat 'de Losbol', we visit a variety of scenery locations along the lakes and canals in Friesland, passing the highlights of Dirk Bootsma's scientific oeuvre. Departing from 'de Fluessen', his homeport, with his PhD work on the effect of X-rays and UV on cell cycle progression, we head for the pioneering endeavours of his team on mapping genes on human chromosomes by cell hybridization. Next we explore the use of cell hybrids by the Bootsma team culminating in the molecular cloning of one of the first chromosomal breakpoints involved in oncogenesis: the bcr-abl fusion gene responsible for chronic myelocytic leukemia. This seminal achievement enabled later development of new methods for early detection and very promising therapeutic intervention. A series of highlights at the horizon constitute the contributions of his team to the field of DNA repair, beginning with the discovery of genetic heterogeneity in the repair syndrome xeroderma pigmentosum (XP) followed later by the cloning of a large number of human repair genes. This led to the discovery that DNA repair is strongly conserved in evolution rendering knowledge from yeast relevant for mammals and vice versa. In addition, it resolved the molecular basis of several repair syndromes and permitted functional analysis of the encoded proteins. Another milestone is the discovery of the surprising connection between DNA repair and transcription initiation via the dual functional TFIIH complex in collaboration with Jean-Marc Egly et al. in Strasbourg. This provided an explanation for many puzzling clinical features and triggered a novel concept in human genetics: the existence of repair/transcription syndromes. The generation of many mouse mutants carrying defects in repair pathways yielded valuable models for assessing the clinical relevance of DNA repair including carcinogenesis and the identification of a link between DNA damage and premature aging. His team also opened a fascinating area of cell biology with the analysis of repair and transcription in living cells. A final surprising evolutionary twist was the discovery that photolyases designed for the light-dependent repair of UV-induced DNA lesions appeared to be adopted for driving the mammalian biological clock. The latter indicates that it is time to return to 'de Fluessen', where we will consider briefly the merits of Dirk Bootsma for Dutch science in general.
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PMID:From xeroderma pigmentosum to the biological clock contributions of Dirk Bootsma to human genetics. 1134 93