Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss or lowered expression of BRCA1 in non-familial breast cancer has been shown in several recent studies. Understanding how BRCA1 expression is regulated should provide new insights into the role of BRCA1 in sporadic breast cancer. We have recently identified a critical 18-base pair (bp) DNA element within the minimal BRCA1 promoter whereupon the formation of a specific protein-DNA complex and transcription of BRCA1 is dependent. We now report a non tissue-specific transcriptional repressor activity, located more than 500 bp into the first intron of BRCA1. Progressive deletions from the 3'-end of intron 1 and reporter gene assays localized the repressor activity to an 83-bp region. Electrophoretic mobility shift assays with this 83 bp DNA and various sub-fragments of it showed binding of nuclear proteins to a 36 bp BstNI-BseRI fragment. Functional transcriptional repression by this 36 bp DNA could be conferred on a heterologous thymidine kinase promoter. Analysis of multiple reporter gene constructs containing the BRCA1 genomic region driving transcription in both directions suggests that the putative negative regulatory element functions to block transcription only in the BRCA1 direction, although the promoter is shared by the divergently transcribed NBR2 gene.
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PMID:Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene. 1131 75

In contrast to hundreds of mutations found in familial breast and/or ovarian cancers, somatic mutations of BRCA1 are very rare. However, a high percentage of sporadic breast and ovarian cancers show a reduction in BRCA1 expression, suggesting that defects in transcriptional regulation is a contributing factor. BRCA1 shares a promoter with its neighboring gene, NBR2, which is transcribed in the opposite direction. We have previously shown that the transcription of BRCA1 is negatively regulated by protein factors that interact with a 36-bp segment, located 575 bp into its first intron. We now report the localization of an 18-bp transcriptional repressor element for NBR2, which resides 948 bp into its first intron. The binding of nuclear proteins to this repressor element was detected by electrophoretic mobility shift assays (EMSAs), and it conferred an orientation-dependent functional suppression onto a heterologous thymidine kinase promoter. Combined with our previous studies, a model of transcriptional regulation of the closely aligned BRCA1-NBR2 bi-directional unit is proposed. A minimal 56-bp DNA region is functional in driving transcription in both directions, while uni-directional control is provided by distinct repressors that bind to sequences located in the first intron of the respective genes.
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PMID:Model of transcriptional regulation of the BRCA1-NBR2 bi-directional transcriptional unit. 1577 33