Tumor Cells Exhibit Deregulation of the Cell Cycle Histone Gene Promoter Factor HiNF-D

Abstract

Cell cycle-regulated gene expression is essential for normal cell growth and development and loss of stringent growth control is associated with the acquisition of the transformed phenotype. The selective synthesis of histone proteins during the S phase of the cell cycle is required to render cells competent for the ordered packaging of replicating DNA into chromatin. Regulation of H4 histone gene transcription requires the proliferation-specific promoter binding factor HiNF-D. In normal diploid cells, HiNF-D binding activity is regulated during the cell cycle; nuclear protein extracts prepared from normal cells in S phase contain distinct and measurable HiNF-D binding activity, while this activity is barely detectable in G1 phase cells. In contrast, in tumor-derived or transformed cell lines, HiNF-D binding activity is constitutively elevated throughout the cell cycle and declines only with the onset of differentiation. The change from cell cycle-mediated to constitutive interaction of HiNF-D with the promoter of a cell growth-controlled gene is consistent with, and may be functionally related to, the loss of stringent cell growth regulation associated with neoplastic transformation.

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 .…”

Expression of N‐terminally truncated isoforms of CDP/CUX is increased in human uterine leiomyomas

“…CUTL1 encodes for the CDP/Cux protein, which was characterized independently as the CDP and the DNA binding subunit of the HiNF-D. [12][13][14] The DNA binding activity of HiNF-D was upregulated in S phase in normal cells but constitutively activated in tumor cell lines. [15][16][17][18] CDP/Cux is a transcription factor that contains 4 DNA binding domains and whose expression has been associated with cellular proliferation, the repression of genes that are turned on in terminally differentiated cells and the regulation of MARs. 19 In addition, the evidence points to a role of CDP/Cux in cell-cycle progression.…”

“…12,13,15,20,21 Moreover, one of the CDP/Cux DNA binding activities is upregulated as normal cells progress into S phase and inhibited in G 2 following phosphorylation of the Cut homeodomain by cyclin A/CDK1. 15,22,23 Upregulation of CDP/Cux DNA binding activity at the G 1 /S transition involves proteolytic processing of p200 CDP/Cux into an Nterminally truncated isoform of 110 kDa. 24 From the point of view of the experimentalist, uterine leiomyomas represent an excellent tumor system for molecular investigation.…”

Phosphorylation of the CCAAT Displacement Protein (CDP)/Cux Transcription Factor by Cyclin A-Cdk1 Modulates Its DNA Binding Activity in G2

“…CDP/Cux was found to be a component of the histone nuclear factor D (HiNF-D), whose presence on various histone promoters coincides with its up-regulation in the cell cycle (28 -31). Interaction of CDP/Cux with a consensus binding site or with histone H4 gene promoter sequences (as part of HiNF-D) was found to be up-regulated as cells progress from G 1 to S phase (32,33). CDP/Cux was shown to bind to the core promoter of the p21 WAF1/CIP1 gene, and in transient transfection assays, CDP/Cux repressed a p21 WAF1/CIP1 reporter, whereas an antisense CDP/Cux construct was able to restore p21 WAF1/CIP1 expression levels in S phase (32).…”