Regulation of Gene Expression and Transcription Factor Binding Activity during Cellular Aging

Meyyappan, Muthupalaniappan; Atadja, Peter; Riabowol, Karl

doi:10.1159/000109183

Cited by 29 publications

(21 citation statements)

References 23 publications

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“…As shown previously, most cells expressing oncogenic ras alone displayed a cytoplasmic staining for phospho-ERK1/2. This finding is consistent with reports indicating that senescent cells do not respond to serum stimulation (28). However, more than half of the cells expressing the anti-PEA-15 hairpin exhibited a predominant nuclear staining of phospho-ERK1/2 (Fig.…”

Section: Pea-15 Erk Localization and Senescencesupporting

confidence: 92%

PEA-15 Is Inhibited by Adenovirus E1A and Plays a Role in ERK Nuclear Export and Ras-induced Senescence

Gaumont-Leclerc

Mukhopadhyay

Goumard

et al. 2004

Journal of Biological Chemistry

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Oncogenic ras activates multiple signaling pathways to enforce cell proliferation in tumor cells. The ERK1/2 mitogen-activated protein kinase pathway is required for the transforming effects of ras, and its activation is often sufficient to convey mitogenic stimulation. However, in some settings oncogenic ras triggers a permanent cell cycle arrest with features of cellular senescence. How the Ras/ERK1/2 pathway activates different cellular programs is not well understood. Here we show that ERK1/2 localize predominantly in the cytoplasm during ras-induced senescence. This cytoplasmic localization seems to be dependent on an active nuclear export mechanism and can be rescued by the viral oncoprotein E1A. Consistent with this hypothesis, we showed that E1A dramatically down-regulated the expression of the ERK1/2 nuclear export factor PEA-15. Also, RNA interference against PEA-15 restored the nuclear localization of phospho-ERK1/2 in Ras-expressing primary murine embryo fibroblasts and stimulated their escape from senescence. Because senescence prevents the transforming effect of oncogenic ras, our results suggest a tumor suppressor function for PEA-15 that operates by means of controlling the localization of phospho-ERK1/2.

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Section: Pea-15 Erk Localization and Senescencesupporting

confidence: 92%

PEA-15 Is Inhibited by Adenovirus E1A and Plays a Role in ERK Nuclear Export and Ras-induced Senescence

Gaumont-Leclerc

Mukhopadhyay

Goumard

et al. 2004

Journal of Biological Chemistry

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“…Changes in the expression patterns of a number of cell cycle-regulatory genes during replicative senescence, some of which are thought to contribute to the senescent phenotype, have been described (42,69 (2,16,21,47,72). Interestingly, we and others have found that the activity of p53 increases in senescent fibroblasts (3,66), perhaps providing a molecular mechanism for the upregulation of D-type cyclins during cellular aging.…”

Section: Waf/cip/sdimentioning

confidence: 66%

Increased Expression of Cyclin D2 during Multiple States of Growth Arrest in Primary and Established Cells

Meyyappan¹,

Wong

Hull³

et al. 1998

Molecular and Cellular Biology

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107

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Cyclin D2 is a member of the family of D-type cyclins that is implicated in cell cycle regulation, differentiation, and oncogenic transformation. To better understand the role of this cyclin in the control of cell proliferation, cyclin D2 expression was monitored under various growth conditions in primary human and established murine fibroblasts. In different states of cellular growth arrest initiated by contact inhibition, serum starvation, or cellular senescence, marked increases (5-to 20-fold) were seen in the expression levels of cyclin D2 mRNA and protein. Indirect immunofluorescence studies showed that cyclin D2 protein localized to the nucleus in G 0 , suggesting a nuclear function for cyclin D2 in quiescent cells. Cyclin D2 was also found to be associated with the cyclin-dependent kinases CDK2 and CDK4 but not CDK6 during growth arrest. Cyclin D2-CDK2 complexes increased in amounts but were inactive as histone H1 kinases in quiescent cells. Transient transfection and needle microinjection of cyclin D2 expression constructs demonstrated that overexpression of cyclin D2 protein efficiently inhibited cell cycle progression and DNA synthesis. These data suggest that in addition to a role in promoting cell cycle progression through phosphorylation of retinoblastoma family proteins in some cell systems, cyclin D2 may contribute to the induction and/or maintenance of a nonproliferative state, possibly through sequestration of the CDK2 catalytic subunit.In eukaryotes, cell proliferation is regulated by the cooperative activity of a set of cell cycle control genes (reviewed in references 56 and 57). These genes include those that encode cyclin-dependent kinases (CDKs) and the proteins that regulate their behavior, cyclins and CDK inhibitors. Analysis of cyclin and CDK inhibitor expression has indicated that phasespecific oscillations in the abundance of some of these proteins are responsible, in part, for the orderly and linear progression of cells through key cell cycle checkpoints. In mammalian cells, an important cell cycle checkpoint called the restriction point is located at a position just prior to the onset of DNA synthesis (51). The expression of a subset of cell cycle control genes occurs during the G 1 phase of the cycle, placing them in a temporal position to influence this key cell cycle decision (56). Among such candidate G 1 control genes are those encoding cyclins D and E and the CDK inhibitors belonging to the p21 WAF/CIP/SDI and p16 INK4 families. The D-type cyclins consist of three family members, cyclins D1, D2, and D3. The cyclin D1 gene was identified as a delayed-early gene that was inducible by colony-stimulating factor (37), by its ability to complement G 1 cyclin-deficient yeast strains (33,74), and as the PRAD-1/bcl-1 proto-oncogene that underwent gene rearrangements, gene amplification, and deregulated expression in a variety of tumor types (reviewed in reference 43). Microinjection experiments with anti-cyclin D1 antibodies have suggested that cyclin D1 may be required for progression ...

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“…3e), however. Third, phosphorylation of SRF by the ribosomal S6 kinase pp90RSK, casein kinase II, or DNA-PK can enhance its transcription-promoting activity and DNA binding (37,(41)(42)(43)(44)(45)(46)(47)(48)(49). Whether differential phosphorylation of SRF contributes to the differences in binding activity observed in our subconfluent or long term serum-deprived cells requires further study.…”

Section: Discussionmentioning

confidence: 91%

Physiological Control of Smooth Muscle-specific Gene Expression through Regulated Nuclear Translocation of Serum Response Factor

Camoretti-Mercado¹,

Liu²,

Halayko³

et al. 2000

Journal of Biological Chemistry

109

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Prolonged serum deprivation induces a structurally and functionally contractile phenotype in about 1/6 of cultured airway myocytes, which exhibit morphological elongation and accumulate abundant contractile apparatus-associated proteins. We tested the hypothesis that transcriptional activation of genes encoding these proteins accounts for their accumulation during this phenotypic transition by measuring the transcriptional activities of the murine SM22 and human smooth muscle myosin heavy chain promoters during transient transfection in subconfluent, serum fed or 7 day serum-deprived cultured canine tracheal smooth muscle cells. Contrary to our expectation, SM22 and smooth muscle myosin heavy chain promoter activities (but not viral murine sarcoma virus-long terminal repeat promoter activity) were decreased in long term serum-deprived myocytes by at least 8-fold. Because serum response factor (SRF) is a required transcriptional activator of these and other smooth muscle-specific promoters, we evaluated the expression and function of SRF in subconfluent and long term serum-deprived cells. Whole cell SRF mRNA and protein were maintained at high levels in serum-deprived myocytes, but SRF transcription-promoting activity, nuclear SRF binding to consensus CArG sequences, and nuclear SRF protein were reduced. Furthermore, immunocytochemistry revealed extranuclear redistribution of SRF in serum-deprived myocytes; nuclear localization of SRF was restored after serum refeeding. These results uncover a novel mechanism for physiological control of smooth muscle-specific gene expression through extranuclear redistribution of SRF and consequent down-regulation of its transcriptionpromoting activity.Confluent cultured, passaged canine tracheal myocytes exhibit divergent phenotypes when deprived of serum for 7 or more days. About 1/6 of these cells accumulate abundant contractile apparatus proteins, increasing whole culture contents of smooth muscle myosin heavy chain (smMHC) 1 and SM22 by 5-7-fold (1, 2). These myocytes acquire a contractile phenotype, characterized by morphological elongation, expression of functionally coupled muscarinic M 3 surface receptors, and substantial contraction (shortening) upon cholinergic stimulation. Presently, the mechanism responsible for this phenotypic differentiation is unknown.In cultured skeletal muscle, differentiation of myoblasts into myotubes depends upon up-regulation of skeletal muscle-specific gene transcription, which results in abundant contractile apparatus protein accumulation (3-6). This precedent in skeletal muscle suggested that similarly enhanced transcription of contractile apparatus genes might account for the substantial smMHC and SM22 accumulation we observed in long term serum-deprived tracheal smooth muscle cells. To test this hypothesis, we assessed transcription from the smMHC and SM22 gene promoters in both preconfluent serum fed and post confluent long term serum-deprived tracheal myocytes. Contrary to our expectation, we found markedly reduced transcription from...

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Regulation of Gene Expression and Transcription Factor Binding Activity during Cellular Aging

Cited by 29 publications

References 23 publications

PEA-15 Is Inhibited by Adenovirus E1A and Plays a Role in ERK Nuclear Export and Ras-induced Senescence

PEA-15 Is Inhibited by Adenovirus E1A and Plays a Role in ERK Nuclear Export and Ras-induced Senescence

Increased Expression of Cyclin D2 during Multiple States of Growth Arrest in Primary and Established Cells

Physiological Control of Smooth Muscle-specific Gene Expression through Regulated Nuclear Translocation of Serum Response Factor

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