Involvement of the cell cycle-regulated nuclear factor HiNF-D in cell growth control of a human H4 histone gene during hepatic development in transgenic mice.

Abstract

Regulation of the cell cycle-controlled histone gene promoter factor HiNF-D was examined in vivo. Proliferative activity was measured by DNA replication-dependent histone mRNA levels, and HiNF-D binding activity was found to correlate with cell proliferation in most tissues. Furthermore, HiNF-D is down-regulated during hepatic development, reflecting the onset of differentiation and quiescence. The contribution of transcription to histone gene expression was directly addressed in transgenic mice by using a set of fusion constructs containing a human H4 histone gene promoter linked to three different genes. Transgene expression in both fetal and adult mice paralleled endogenous mouse histone mRNA levels in most tissues, consistent with this promoter conferring developmental, cell growth-related transcriptional regulation. Our results suggest that HiNF-D is stringently regulated in vivo in relation to cell growth and support a primary role for HiNF-D in the proliferation-specific expression of H4 histone genes in the intact animal. Further, the data presented here provide an example in which apparent tissue specificity of gene expression reflects the proliferative state of various tissues and demonstrate that multiple levels of histone gene regulation are operative in vivo.

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

“…We propose that p110 CDP/Cux plays a role in the establishment of at least part of the S-phase-specific transcription program and that CDP/Cux does not act alone in the regulation of S-phase-specific genes but rather functions in combinatorial fashion with other transcription factors. This mode of action would be entirely consistent with known features of the HiNF-D complex, which resides on the promoter of histone genes during S phase (4,5,30,(68)(69)(70)(71)(72). Moreover, this mechanism of action would explain why cells reach S phase faster in the presence of p110 CDP/Cux but are still able to proliferate in its absence, albeit more slowly.…”

“…DNA binding decreased later in the cell cycle following phosphorylation of serine 1237 by cyclin A/Cdk1 (58). Moreover, a large body of evidence demonstrated that the HiNF-D complex, of which CDP/Cux is the primary DNA binding protein, is active in S phase (22,69,(71)(72)(73).…”

“…In addition, a role for CDP/Cux specifically in the S phase of the cell cycle has been inferred from a number of reports. Histone nuclear factor D (HiNF-D), which was later found to include CDP/Cux as its DNA binding partner, was shown to be up-regulated in S phase in normal cells (22,69,(71)(72)(73). Up-regulation of CDP/Cux DNA binding at the G 1 /S transition was found to result from at least two posttranslational modifications: dephosphorylation of the Cut homeodomain by the Cdc25A phosphatase (11) and proteolytic cleavage of p200 CDP/Cux between CR1 and CR2 to generate N-terminally truncated p110 CDP/Cux (16,45).…”

Histone gene transcription: A model for responsiveness to an integrated series of regulatory signals mediating cell cycle control and proliferation/differentiation interrelationships

“…6: Cellular levels of transcription factors during the cell cycle. The switch from stringent cell-cycle regulated (S-phase restricted) occupancy at Site I1 of the histone gene promoter in normal diploid cells is schematically compared to constitutive occupancy at Site II during the cell cycle in transformed and tumor cells [Holthuis et al, 1991;Paulietal., 19871. …”

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.…”