Histone gene expression remains coupled to DNA synthesis during in vitro cellular senescence

Zambetti, Gerard P.; Dell’Orco, Robert T.; Stein, Gary S.

doi:10.1016/0014-4827(87)90397-1

Cited by 13 publications

(4 citation statements)

References 24 publications

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“…2B). These results support the finding that DNA synthesis and histone expression remain coupled as neonatal human fibroblasts senesce (23) and suggest that, like pHE-7, the replication-dependent histone genes are repressed in senescent cells.…”

supporting

confidence: 86%

Repression of c- fos Transcription and an Altered Genetic Program in Senescent Human Fibroblasts

Seshadri

Campisi

1990

Science

449

203

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Normal cells in culture invariably undergo senescence, whereby they cease proliferation after a finite number of doublings. Irreversible changes in gene expression occurred in senescent human fetal lung fibroblasts: a non-cell cycle-regulated mRNA was partially repressed; an unusual polyadenylated histone mRNA was expressed; although serum induced c-H-ras, c-myc, and ornithine decarboxylase mRNA normally, ornithine decarboxylase activity was deficient; and serum did not induce mRNA for a replication-dependent histone and for the c-fos proto-oncogene. The loss of c-fos inducibility was the result of a specific, transcriptional block. The results suggest that senescent fibroblasts were unable to proliferate because of, at least in part, selective repression of c-fos; moreover, the multiple changes in gene expression support the view that cellular senescence is a process of terminal differentiation.

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supporting

confidence: 86%

Repression of c- fos Transcription and an Altered Genetic Program in Senescent Human Fibroblasts

Seshadri

Campisi

1990

Science

449

203

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“…Our findings that cellular levels of mRNA transcripts from cell cycle regulated histone genes are tightly coupled with DNA replication in osteoblasts and osteosarcoma cells following inhibition of DNA synthesis is in agreement with studies carried out with a broad spectrum of cell types which have demonstrated that inhibition of DNA synthesis by hydroxyurea, aphidi-Colin or cytosine arabinoside [Sittman et al, 1983;Gallwitz and Mueller, 1969;Sourlingas et al, 1991;Sariban et al, 1985;Baumbach et al, 19841 in histone mRNA levels from the cytoplasm [Baumbach et al, 1984[Baumbach et al, , 1987Sittman et al, 1983;Sariban et al, 1985;Zambetti et al, 19871. While the effect of DNA synthesis inhibition on histone mRNA levels is well documented, our understanding of effects on histone gene transcription rates are limited and appear to be dependent on the cell type [DeLisle et al, 1983;Baumbach et al, 1987;Morris et al, 1991;Sittman et al, 1983;Zambetti et al, 1987;Harris et al, 19911. Baumbach et al [1984] demonstrated that hydroxyurea treatment of HeLa cells minimally affected histone gene transcription, which remained at approximately 80% of control levels.…”

Section: Discussionmentioning

confidence: 99%

Influence of DNA replication inhibition on expression of cell growth and tissue‐specific genes in osteoblasts and osteosarcoma cells

Kockx

McCabe

Stein

et al. 1994

J of Cellular Biochemistry

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Interrelationships between proliferation and expression of cell growth as well as bone cell-related genes were examined from two standpoints. First, the consequence of downregulating proliferation by DNA synthesis inhibition on expression of a cell cycle-regulated histone gene and genes associated with development of the bone cell phenotype (type I collagen, alkaline phosphatase, osteopontin, and osteocalcin) was investigated. Second, the requirement for stringent growth control to support functional relationships between expression of proliferation and differentiation-related genes was explored. Parameters of cell growth and osteoblast-related gene expression in primary cultures of normal diploid osteoblasts, that initially express proliferation-dependent genes and subsequently postproliferative genes associated with mature bone cell phenotypic properties, were compared to those operative in ROS 17/2.8 osteosarcoma cells that concomitantly express cell growth and mature osteoblast phenotypic genes. Our findings indicate that in both normal diploid osteoblasts and osteosarcoma cells, expression of the cell cycle regulated histone genes is tightly coupled with DNA synthesis and controlled predominantly at a posttranscriptional level. Inhibition of proliferation by blocking DNA synthesis with hydroxyurea upregulates a subset of developmentally expressed genes that postproliferatively support progressive establishment of mature osteoblast phenotypic properties (e.g., alkaline phosphatase, type 1 collagen, and osteopontin). However, the osteocalcin gene, which is expressed during the final stage of osteoblast differentiation when extracellular matrix mineralization occurs, is not upregulated. Variations in the extent to which inhibition of proliferation in normal diploid osteoblasts and in ROS 17/2.8 osteosarcoma cells selectively affects transcription and cellular levels of mRNA transcripts from bone cell-related genes (e.g., osteocalcin) may reflect modifications in proliferation/differentiation interrelationships when stringent growth control is abrogated.

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“…Labeled cells were scraped into cold phosphate-buffered saline, pelleted by low-speed centrifugation, and resuspended in high-salt buffer (50 mM Na2HP04 and 2.0 M NaCl, pH 7.4). An aliquot of the cell suspension was used for the determination of DNA by the method of Labarca and Paigen (1980), and acid-precipitable radioactivity was determined in a second aliquot as previously described (Zambetti et al, 1987).…”

Section: Methodsmentioning

confidence: 99%

“…mRNA Isolation. Total cellular mRNA was isolated essentially as described previously (Zambetti et al, 1987). SI Nuclease Analysis.…”

Section: Methodsmentioning

confidence: 99%

Multiple mechanisms regulate the proliferation-specific histone gene transcription factor HiNF-D in normal human diploid fibroblasts

et al. 1992

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The proliferation-specific transcription factor complex HiNF-D interacts with sequence specificity in a proximal promoter element of the human H4 histone gene FO108, designated Site II. The occupancy of Site II by HiNF-D has been implicated in proper transcription initiation and as a component of the cell cycle regulation of this gene. In the present study we have investigated the role of the HiNF-D/Site II interaction in controlling the level of H4 histone gene transcription during modifications of normal cellular growth. HiNF-D binding activity is present at high levels in rapidly proliferating cultures of human diploid fibroblasts and is reduced to less than 2% upon the cessation of proliferation induced by serum deprivation of sparsely population fibroblast cultures. Density-dependent quiescence also abolishes HiNF-D binding activity. Downregulation of transcription from the H4 gene occurs concomitant with the loss of the HiNF-D/Site II interaction, further suggesting a functional relationship between Site II occupancy and the capacity for transcription. Serum stimulation of quiescent preconfluent cells results in an increase in HiNF-D binding activity as the cells are resuming DNA synthesis and H4 histone gene transcription. Density-inhibited quiescent cells respond to serum stimulation with only a minimal increase in the HiNF-D binding activity, 30% of maximal levels. However, H4 histone gene transcription is stimulated to a level equal to that detected in extracts of the sparsely populated serum-stimulated cultures. These results suggest that there is a threshold level of HiNF-D binding activity necessary for the activation of H4 histone gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)

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Histone gene expression remains coupled to DNA synthesis during in vitro cellular senescence

Cited by 13 publications

References 24 publications

Repression of c- fos Transcription and an Altered Genetic Program in Senescent Human Fibroblasts

Repression of c- fos Transcription and an Altered Genetic Program in Senescent Human Fibroblasts

Influence of DNA replication inhibition on expression of cell growth and tissue‐specific genes in osteoblasts and osteosarcoma cells

Multiple mechanisms regulate the proliferation-specific histone gene transcription factor HiNF-D in normal human diploid fibroblasts

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