Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two isoforms of the CCAAT-displacement protein/cut homeobox (CDP/Cux) transcription factor have been characterized thus far. The full length protein, p200, which contains four DNA binding domains, transiently binds to DNA and carries the CCAAT-displacement activity. The p110 isoform is generated by proteolytic processing at the G1-S transition and is capable of stable interaction with DNA. Here we demonstrate the existence of a shorter CDP/Cux isoform, p75, which contains only two DNA binding domains, Cut repeat 3 and the Cut homeodomain, and binds more stably to DNA. CDP/Cux p75 was able to repress a reporter carrying the promoter for the cyclin-dependent kinase inhibitor p21 gene and to activate a DNA polymerase alpha gene reporter. Expression of CDP/Cux p75 involved a novel mechanism: transcription initiation within intron 20. The intron 20-initiated mRNA (I20-mRNA) was expressed at higher level in the thymus and in CD4+/CD8+ and CD4+ T cells. I20-mRNA was expressed only weakly or not at all in normal human mammary epithelial cells and normal breast tissues but was detected in many breast tumor cells lines and breast tumors. In invasive tumors a significant association was established between higher I20-mRNA expression and a diffuse infiltrative growth pattern (n = 41, P = 0.0137). In agreement with these findings, T47D breast cancer cells stably expressing p75 could not form tubule structures in collagen but rather developed as solid undifferentiated aggregates of cells. Taken together, these results suggest that aberrant expression of the CDP/Cux p75 isoform in mammary epithelial cells may be associated with the process of tumorigenesis in breast cancer.
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PMID:Characterization of a tissue-specific CDP/Cux isoform, p75, activated in breast tumor cells. 1243 59

CDP/Cux (CCAAT-displacement protein/cut homeobox) contains four DNA binding domains, namely, three Cut repeats (CR1, CR2, and CR3) and a Cut homeodomain. CCAAT-displacement activity involves rapid but transient interaction with DNA. More stable DNA binding activity is up-regulated at the G(1)/S transition and was previously shown to involve an N-terminally truncated isoform, CDP/Cux p110, that is generated by proteolytic processing. CDP/Cux has been previously characterized as a transcriptional repressor. However, here we show that expression of reporter plasmids containing promoter sequences from the human DNA polymerase alpha (pol alpha), CAD, and cyclin A genes is stimulated in cotransfections with N-terminally truncated CDP/Cux proteins but not with full-length CDP/Cux. Moreover, expression of the endogenous DNA pol alpha gene was stimulated following the infection of cells with a retrovirus expressing a truncated CDP/Cux protein. Chromatin immunoprecipitation (ChIP) assays revealed that CDP/Cux was associated with the DNA pol alpha gene promoter specifically in the S phase. Using linker scanning analyses, in vitro DNA binding, and ChIP assays, we established a correlation between binding of CDP/Cux to the DNA pol alpha promoter and the stimulation of gene expression. Although we cannot exclude the possibility that stimulation of gene expression by CDP/Cux involved the repression of a repressor, our data support the notion that CDP/Cux participates in transcriptional activation. Notwithstanding its mechanism of action, these results establish CDP/Cux as an important transcriptional regulator in the S phase.
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PMID:CDP/Cux stimulates transcription from the DNA polymerase alpha gene promoter. 1266 98

CCAAT-displacement protein/Cut homeobox (CDP/Cux) was initially identified as a transcriptional repressor. However, a number of studies have now suggested that CDP/Cux is a transcriptional activator as well. Stable DNA binding activity of CDP/Cux is up-regulated at the G(1)/S transition by two mechanisms, dephosphorylation by the Cdc25A phosphatase and proteolytic processing to generate a 110 kDa amino-truncated isoform, CDP/Cux p110. The generation of CDP/Cux p110 stimulates the expression of reporter plasmid containing the promoter sequences of some S phase-specific-genes such as DNA polymerase a gene, dihydrofolate reductase gene, carbamoyl-phosphate synthase/aspartate carbamoyl-transferase/dihydroorotase gene, and cyclin A gene. However, DNA binding activity of CDP/Cux is down-regulated at G(2) phase through a binding of cyclin A-cyclin-dependent kinases1 (Cdk1) to CDP/Cux. Furthermore, another CDP/Cux isoform, CDP/Cux p75, has been found to be associated with breast tumors indicating this isoform is involved in the abnormal proliferation of tumor cells. The differences in DNA binding of CDP/Cux isoforms in S and G(2) phases suggest important roles of CDP/Cux in cell cycle progression. In this review, we discuss the functions of CDP/Cux with a focus on its roles in cell cycle regulation and its possible potency leading to the cell cycle reentry of neurons.
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PMID:Contribution of CDP/Cux, a transcription factor, to cell cycle progression. 1806 84