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)

Werner syndrome (WS) is characterized by the premature occurrence of many age-related features. Before the cloning of the gene for WS (WRN), several reports suggested that transcriptional defects of genes may relate to the mechanisms of the occurrence of WS and natural aging. Because WRN, which encodes a helicase (WRN-H), has been cloned, we are attempting to clarify the mechanism of the transcriptional abnormalities found in WS cells, using WRN and WRN-H. In this article, we studied transcriptional activation of a promoter by WRN-H in a yeast assay system as a first step. The results showed that WRN-H functions as a transcriptional activator in the system. Furthermore, we performed additional transcriptional assays using various parts of WRN to define the critical region of WRN-H for transcriptional activation in yeast. The results revealed the critical region for the activation most likely mapped to the region of 315 to 403 aa. The region of 404 to 1309 aa may also effect activation in the presence of the critical region. The two regions contain an acidic domain, and the region of 404 to 1309 aa also contains a helicase domain. If this transcriptional activation by WRN-H occurs also in human cells in vivo, direct activation of the promoters by WRN-H could explain the results of somatic cell hybrid studies as well as the overexpressed genes detected in WS cells. However, our results should be interpreted with caution, because thus far, the transcriptional activation by WRN-H were only demonstrated using one promoter in a yeast system.
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PMID:Transcriptional activation by the Werner syndrome gene product in yeast. 995 24

Werner syndrome (WS) is a human progeroid syndrome characterized by the early onset of a large number of clinical features associated with the normal aging process. The complex molecular and cellular phenotypes of WS involve characteristic features of genomic instability and accelerated replicative senescence. The gene involved (WRN) was recently cloned, and its gene product (WRNp) was biochemically characterized as a helicase. Helicases play important roles in a variety of DNA transactions, including DNA replication, transcription, repair, and recombination. We have assessed the role of the WRN gene in transcription by analyzing the efficiency of basal transcription in WS lymphoblastoid cell lines that carry homozygous WRN mutations. Transcription was measured in permeabilized cells by [3H]UTP incorporation and in vitro by using a plasmid template containing the RNA polymerase II (RNA pol II)-dependent adenovirus major late promoter. With both of these approaches, we find that the transcription efficiency in different WS cell lines is reduced to 40-60% of the transcription in cells from normal individuals. This defect can be complemented by the addition of normal cell extracts to the chromatin of WS cells. Addition of purified wild-type WRNp but not mutated WRNp to the in vitro transcription assay markedly stimulates RNA pol II-dependent transcription carried out by nuclear extracts. A nonhelicase domain (a direct repeat of 27 amino acids) also appears to have a role in transcription enhancement, as revealed by a yeast hybrid-protein reporter assay. This is further supported by the lack of stimulation of transcription when mutant WRNp lacking this domain was added to the in vitro assay. We have thus used several approaches to show a role for WRNp in RNA pol II transcription, possibly as a transcriptional activator. A deficit in either global or regional transcription in WS cells may be a primary molecular defect responsible for the WS clinical phenotype.
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PMID:The Werner syndrome protein is involved in RNA polymerase II transcription. 1043 20