Loss of serum response element-binding activity and hyperphosphorylation of serum response factor during cellular aging.

Atadja, Peter; Stringer, K F; Riabowol, Karl

doi:10.1128/mcb.14.7.4991

Cited by 48 publications

(52 citation statements)

References 45 publications

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“…There has been considerable recent progress in identifying the effector pathways by which HDF are held in the senescent state (3,5,21,31,32,52,62,68,70,76,77). These pathways are not unique to senescence but rather represent the coordinated action of gene products that are also believed to play critical roles in quiescence, response to DNA damage, and terminal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Ogryzko

Hirai

Russanova

et al. 1996

Molecular and Cellular Biology

244

153

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Human diploid fibroblasts (HDF) complete a limited number of cell divisions before entering a growth arrest state that is termed replicative senescence. Two histone deacetylase inhibitors, sodium butyrate and trichostatin A, dramatically reduce the HDF proliferative life span in a manner that is dependent on one or more cell doublings in the presence of these agents. Cells arrested and subsequently released from histone deacetylase inhibitors display markers of senescence and exhibit a persistent G 1 block but remain competent to initiate a round of DNA synthesis in response to simian virus 40 T antigen. Average telomere length in prematurely arrested cells is greater than in senescent cells, reflecting a lower number of population doublings completed by the former. Taken together, these results support the view that one component of HDF senescence mimics a cell cycle-dependent drift in differentiation state and that propagation of HDF in histone deacetylase inhibitors accentuates this component.Cellular senescence in human diploid fibroblasts (HDF) and other human cell types has been extensively studied (17,26,35,53,73,85) yet remains incompletely understood. On the basis of current knowledge, it is not unreasonable to suppose that multiple mechanisms contribute to the senescence phenotype and that the relative contributions of such mechanisms may vary for different cell types and conditions of cell propagation. At least two senescence-associated changes, increased oxidative stress (74, 75) and telomere shortening (33,34,55,87), have been intensively studied and are widely viewed as important components of in vitro aging. Less well studied is a third aspect of senescence, namely, its apparent relatedness to differentiation (4,16,26,48,57). Although these two processes are not necessarily synonymous (60, 88), in many respects senescence resembles a partial or aberrant form of terminal differentiation, with cells appearing to acquire a phenotype that is suboptimal for tissue function and maintenance. HDF proliferative potential is dependent primarily on the number of rounds of DNA synthesis completed rather than the cumulative time in culture (17,19,27); thus, to the extent that senescence is akin to terminal differentiation, it most closely resembles model systems (e.g., murine erythroleukemia or promyelocytic leukemia cells) where a requirement for passage through the cell cycle has been demonstrated (7,45,46).Our attention to the differentiative aspects of senescence was first prompted by experiments designed to compare cell cycle arrest mechanisms in senescent and quiescent cells. Transient expression of simian virus 40 (SV40) T antigen is strongly mitogenic, i.e., is dominant over cell cycle arrest mechanisms, in both senescent cells and serum-deprived quiescent fibroblasts (29,39,80). We and others observed that in senescent HDF, but not quiescent cells, the domain in T antigen which mediates binding to retinoblastoma (Rb) family proteins is required for efficient stimulation of DNA synthesis (8a, 65). This...

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Section: Discussionmentioning

confidence: 99%

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Ogryzko

Hirai

Russanova

et al. 1996

Molecular and Cellular Biology

244

153

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“…Using nuclear extracts isolated from 4-day growth-arrested fibroblasts, we obtained the same three bands A, B, and D. However, when compared with nuclear extracts from growing cells, band B was greatly reduced in intensity and an additional band C of faster mobility was observed. Hyperphosphorylation of SRF is thought to be responsible for the inability of SRF to bind the SRE in senescent human fibroblasts (83). It is possible that, in growth-arrested fibroblasts, the transcription of the apoD gene is elicited due to inactivation of SRF by hyperphosphorylation, which, in turn, allows other factors such as stress proteins to bind to the SRE and transactivate expression (Band C).…”

Section: Mapping Of the Functional Elements Associated With The Growtmentioning

confidence: 99%

Modulation of Apolipoprotein D and Apolipoprotein E mRNA Expression by Growth Arrest and Identification of Key Elements in the Promoter

Carmo

Séguin

Milne

et al. 2002

Journal of Biological Chemistry

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Apolipoprotein D (apoD) and apolipoprotein E (apoE) are co-expressed in many tissues, and, in certain neuropathological situations, their expression appears to be under coordinate regulation. We have previously shown that apoD gene expression in cultured human fibroblasts is up-regulated when the cells undergo growth arrest. Here, we demonstrate that, starting around day 2 of growth arrest, both apoD and apoE mRNA levels increase between 1.5-and 27-fold in other cell types, including mouse primary fibroblasts and fibroblast-like and human astrocytoma cell lines. To understand the regulatory mechanisms of apoD expression, we have used apoD promoter-luciferase reporter constructs to compare gene expression in growing cells and in cells that have undergone growth arrest. Analysis of gene expression in cells transfected with constructs with deletions and mutations in the apoD promoter and constructs with artificial promoters demonstrated that the region between nucleotides ؊174 and ؊4 is fully responsible for the basal gene expression, whereas the region from ؊558 to ؊179 is implicated in the induction of apoD expression following growth arrest. Within this region, an alternating purine-pyrimidine stretch and a pair of serum-responsive elements (SRE) were found to be major determinants of growth arrest-induced apoD gene expression. Evidence is also presented that SREs in the apoE promoter may contribute to the up-regulation of apoE gene expression following growth arrest.

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“…Hyperphosphorylation of serum response factor in senescent cells has been proposed as a cause of repressed c-fos gene expression (2). Another notable aspect is the shortening of the telomeres accompanying cell division, which has been proposed as a molecular clock of division potential (11,62).…”

mentioning

confidence: 99%

Induction of Senescence-Like Phenotypes by Forced Expression of hic-5, Which Encodes a Novel LIM Motif Protein, in Immortalized Human Fibroblasts

Shibanuma

Mochizuki

Maniwa

et al. 1997

Molecular and Cellular Biology

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The hic-5 gene encodes a novel protein with Zn finger-like (LIM) motifs, the expression of which increases during cellular senescence. The ectopic expression of hic-5 in nontumorigenic immortalized human fibroblasts, whose expression levels of hic-5 were significantly reduced in comparison with those of mortal cells, decreased colony-forming efficiency. Stable clones expressing high levels of hic-5 mRNA showed higher levels of mRNAs for several extracellular matrix-related proteins, along with the alteration of an alternative splicing as seen in senescent cells and decreased c-fos inducibility. Furthermore, these clones acquired a senescence-like phenotype, such as growth retardation; senescence-like morphology; and increased expression of Cip1/WAF1/sdi1 after 20 to 40 population doublings. On the other hand, antisense RNA expression of hic-5 in human normal diploid fibroblasts delayed the senescence process. HIC-5 was localized in nuclei and had affinity for DNA. Based on these observations, we speculated that HIC-5 affected the expression of senescence-related genes through interacting with DNA and thereby induced the senescence-like phenotypes. To our knowledge, hic-5 is the first single gene that could induce senescence-like phenotypes in a certain type of immortalized human cell and mediate the normal process of senescence.

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Loss of serum response element-binding activity and hyperphosphorylation of serum response factor during cellular aging.

Cited by 48 publications

References 45 publications

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Human Fibroblast Commitment to a Senescence-Like State in Response to Histone Deacetylase Inhibitors Is Cell Cycle Dependent

Modulation of Apolipoprotein D and Apolipoprotein E mRNA Expression by Growth Arrest and Identification of Key Elements in the Promoter

Induction of Senescence-Like Phenotypes by Forced Expression of hic-5, Which Encodes a Novel LIM Motif Protein, in Immortalized Human Fibroblasts

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