Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a result of the t(11;22)(q24;q12) chromosomal translocation characterizing the Ewing family of tumors (ET), the amino terminal portion of EWS, an RNA binding protein of unknown function, is fused to the DNA-binding domain of the ets transcription factor Fli1. The hybrid EWS-Fli1 protein acts as a strong transcriptional activator and, in contrast to wildtype Fli1, is a potent transforming agent. Similar rearrangements involving EWS or the highly homologous TLS with various transcription factors have been found in several types of human tumors. Employing yeast two-hybrid cloning we isolated the seventh largest subunit of human RNA polymerase II (hsRPB7) as a protein that specifically interacts with the amino terminus of EWS. This association was confirmed by in vitro immunocoprecipitation. In nuclear extracts, hsRPB7 was found to copurify with EWS-Fli1 but not with Fli1. Overexpression of recombinant hsRPB7 specifically increased gene activation by EWS-chimeric transcription factors. Replacement of the EWS portion by hsRPB7 in the oncogenic fusion protein restored the transactivating potential of the chimera. Our results suggest that the interaction of the amino terminus of EWS with hsRPB7 contributes to the transactivation function of EWS-Fli1 and, since hsRPB7 has characteristics of a regulatory subunit of RNA polymerase II, may influence promoter selectivity.
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PMID:Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. 970 26

Bleomycin is an antitumor drug that kills cells by introducing lesions in DNA. Thus, normal cells exposed to bleomycin must rely on efficient DNA repair mechanisms to survive. In the yeast Saccharomyces cerevisiae, the transcriptional activator Imp2 is required to fend off the toxic effects of bleomycin. However, it remains unclear whether Imp2 controls the expression of a protein that either repairs bleomycin-induced DNA lesions, or detoxifies the drug, and or both. To gain further insight into the mechanisms by which yeast cells mount a response towards bleomycin, we began to sequentially characterize the genetic defect in a collection of bleomycin-sensitive mutants that were previously isolated by mini-Tn3 transposon mutagenesis. A rescue plasmid designed to integrate at the site of the mini-Tn3 insertion was used to identify the defective gene in one of the mutant strains, HCY53, which was not allelic to IMP2. We showed that in strain HCY53, the mini-Tn3 was inserted at the distal end of an essential gene RPB7, which encodes one of the two subunits, Rpb4-Rbp7, that forms a subcomplex with RNA polymerase II. Since rpb7 null mutants are nonviable, it would appear that the rpb7::mini-Tn3 allele produces a protein that retains partial biological function thus permitting cell viability, but which is unable to provide bleomycin resistance to strain HCY53. The defective phenotype of strain HCY53 could be corrected by a plasmid bearing the entire RPB7 gene. Two dimensional gel analysis revealed that the expression of several proteins were diminished or absent in the rpb7::mini-Tn3 mutant when challenged with bleomycin. These results are in accord with our previous report that bleomycin resistance in yeast is controlled at the transcriptional level.
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PMID:An allele of the yeast RPB7 gene, encoding an essential subunit of RNA polymerase II, reduces cellular resistance to the antitumor drug bleomycin. 1054 1