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)

The proximal CCAAT element located 38 bp upstream of the transcription initiation site contributes to the human thymidine kinase (htk) promoter activity, because site-directed mutagenesis of a 10-bp region containing this CCAAT motif (TKC1) reduced the promoter activity by 55%. Through binding site competitions and antigenic cross-reactivity, the major factor that binds TKC1 from both HeLa and hamster nuclear extracts is identified as NF-Y/CBF. In serum-stimulated cells, the binding of NF-Y/CBF to TKC1 increased gradually, reaching a plateau at the S phase. In cell transfection assays, a dominant-negative mutant of NF-Y/CBF inhibited the htk promoter in a dosage-dependent manner, providing direct evidence that NF-Y/CBF is required for maximal htk promoter activity. Recently, it has been demonstrated that the site occupied by NF-Y/CBF also binds the serum-inducible dbpA and dpbB. We show here that recombinant dbpA interacts with the htk promoter, and overexpression of dbpA can stimulate htk promoter activity mediated through TCK1. In contrast, CDP/cut, the CCAAT displacement protein with known repressor property, binds the htk promoter through both the proximal and distal CCAAT elements. Our discovery that CDP/cut binds the htk promoter primarily in quiescent cells and that overexpression of CDP/cut inhibits htk promoter activity provides an explanation for the reported dramatic increase in htk promoter activity in serum-starved cells when both CCAAT elements were mutated. Thus, a combination of suppression in quiescent cells and activation in serum-stimulated cells mediated through various CCAAT-binding proteins may account in part for the induction of htk promoter activity as quiescent cells reenter the cell cycle.
 ...
PMID:Positive and negative regulation of the human thymidine kinase promoter mediated by CCAAT binding transcription factors NF-Y/CBF, dbpA, and CDP/cut. 941 21

The coding region of the human histone H4 gene FO108 undergoes dynamic changes in chromatin structure that correlate with modifications in gene expression. Such structural alterations generally reflect transcription factor interactions with gene regulatory sequences. To test for regulatory elements within the coding region, we performed transient transfection experiments in HeLa cells using constructs with histone H4 sequences fused upstream of a heterologous thymidine kinase promoter and CAT reporter gene. H4 gene sequences from -10 to +210 repressed transcription 4.8-fold. Further deletion and mutational analysis delineated three repressor elements within this region. Using oligonucleotide competition analysis and specific antibody recognition in electrophoretic mobility shift assays, as well as methylation interference and DNase I footprinting analyses, we have identified the CCAAT displacement protein (CDP/cut) as the factor that interacts with these three repressor elements. CDP/cut binding to these repressor sites is proliferation-specific and cell-cycle-regulated, increasing in mid to late S phase. Our results indicate that the proximal 200 nucleotides of the histone H4-coding region contain transcriptional regulatory elements that may contribute to cell-cycle control of histone gene expression by interacting with repressor complexes containing CDP/cut homeodomain transcription factors.
 ...
PMID:Repressor elements in the coding region of the human histone H4 gene interact with the transcription factor CDP/cut. 987 97

The CCAAT displacement protein/cut homologue (CDP/cut) is a divergent homeodomain protein that is highly conserved through evolution and has properties of a potent transcriptional repressor. CDP/cut contains three conserved cut-repeat domains and a conserved homeobox, each involved in directing binding specificity to unique nucleotide sequence elements. Furthermore, CDP/cut may play a role as a structural component of chromatin through its direct interaction with nucleosomal DNA and association with nuclear matrix attachment regions. CDP/cut is cell-cycle regulated through interactions with Rb, p107, specific kinases and phosphatases directing the transcriptional activity of CDP/cut on such genes encoding p21(WAF1,CIP1), c-myc, thymidine kinase, and histones. Our previous studies indicate that CDP/cut is associated with histone deacetylase activity and is associated with a corepressor complex through interactions with histone deacetylases. Here, we report the interaction of CDP/cut with CBP and p300/CREB-binding protein-associated factor (PCAF) along with the modification of CDP/cut by the histone acetyltransferase PCAF. Acetylation of CDP/cut by PCAF is directed at conserved lysine residues near the homeodomain region and regulates CDP/cut function. These observations are consistent with the ability of CDP/cut to regulate genes as a transcriptional repressor, suggesting acetylation as a mechanism that regulates CDP/cut function.
 ...
PMID:Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP. 1085 58