CDP/Cux Stimulates Transcription from the DNA Polymerase α Gene Promoter

The p110 Isoform of the CDP/Cux Transcription Factor Accelerates Entry into S Phase

“…An additional function of the protein is activated following a proteolytic processing event that generates the p110 isoform (16,45). This protein makes a stable interaction with DNA and is able to stimulate the expression of several genes whose products are required for DNA replication (45,65). At a cellular level, p110 accelerates entry into S phase and stimulates cell proliferation.…”

“…At the end of the G 1 phase of the cell cycle, proteolytic cleavage of p200 generates p110 CDP/Cux, which contains CR2CR3HD and exhibits distinct DNA binding specificity and kinetics (45). In particular, p110 but not p200 was shown to activate a DNA polymerase ␣ gene reporter in transient-transfection assays and to stimulate expression of the endogenous DNA polymerase ␣ gene following the infection of cells with a high-titer retrovirus (45,65).…”

“…The protease responsible for proteolytic processing of CDP/Cux was shown to be a nuclear isoform of cathepsin L that is devoid of a signal peptide (16). The processed isoform, p110, was found to participate in the transcriptional activation of the DNA polymerase ␣ gene and, at least in reporter assays, of a number of genes that are up-regulated in S phase, like the dihydrofolate reductase, carbamoyl-phosphate synthase/aspartate carbamoyl-transferase/dihydroorotase, B-Myb, and cyclin A genes (65). The activity of the p110 isoform is confined primarily to the S phase of the cell cycle.…”

“…Cyclin A2 is a direct target of CDP/Cux. Previous studies implicating cyclin A2 as a potential target of CDP/Cux were limited to reporter assays (65). To verify whether CDP/Cux is present on the endogenous cyclin A2 promoter, we performed chromatin immunoprecipitation assays using cells from the Hs578T breast tumor cell line, which is known to express high levels of several CDP/Cux isoforms (17).…”

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

“…It is not possible to evaluate the experimental evidence, as the gene list was not provided. Certainly, the idea that CUX1 represses genes that are involved in cell cycle progression runs contrary to the bulk of the evidence showing that CUX1 stimulates expression of histone genes and many genes involved in DNA replication, while repressing expression of the cyclin-dependent kinase inhibitors p21 and p27 (REFS 15,41,60,62,(68)(69)(70)(71)(72)(73)(74)(75). Moreover, in cell-based assays, MEFs from Cux1-knockout mice showed a longer G1 phase and proliferated more slowly than their wild-type counterparts; whereas, in many cell types, ectopic expression of p110 CUX1 accelerated S phase entry and stimulated proliferation 21,22 .…”