Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells.

Pearson, Barbara E.; Nasheuer, Heinz-Peter; Wang, Teresa S.‐F.

doi:10.1128/mcb.11.4.2081

Cited by 212 publications

(125 citation statements)

References 61 publications

(60 reference statements)

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“…In response to growth stimulation, the expression of genes whose products are involved in DNA replication, including those for pol a and DNA primase, increases dramatically at late G1 (Baserga, 1991;Miyazawa et al, 1993). The cell cycle-regulatory transcription factor E2F-1, which binds to the speci®c recognition site 5'-TTTCGCGC, activates the promoters of the pol a gene and other genes that encode proteins required for DNA replication and cell growth, including those encoding dihydrofolate reductase, thymidine kinase, c-MYC, c-MYB, PCNA, cyclin D, and cyclin E (Blake and Azizkhan, 1989;DeGregori et al, 1995;Nevins, 1992;Pearson et al, 1991;Slansky et al, 1993). The E2F-1 gene promoter also contains E2F binding sites, and E2F-1 activates transcription of its own gene during the cell cycle by binding to these sites (Neuman et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…To investigate further the mechanism by which PARP contributes to regulation of pol a gene transcription during early S phase, we examined the e ect of PARP depletion by gene knockout on the abundance of E2F-1, a transcription factor that positively regulates the transcription of several genes whose products are required for DNA replication and cell growth; these genes include those encoding pol a, PCNA, dihydrofolate reductase, thymidine kinase, c-MYC, c-MYB, cyclin D, cyclin E, and E2F-1 itself (Blake and Azizkhan, 1989;DeGregori et al, 1995;Nevins, 1992;Pearson et al, 1991;Slansky et al, 1993). We previously demonstrated that PARP depletion by antisense RNA expression in 3T3-L1 cells prevents induction of E2F-1 expression during the early stages of di erentiation-linked DNA replication (SimbulanRosenthal et al, 1998a).…”

Section: Parp7/7 Cells Do Not Show the Marked Induction Of E2f-1 Exprmentioning

confidence: 99%

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Poly(ADP-ribose) polymerase upregulates E2F-1 promoter activity and DNA pol α expression during early S phase

et al. 1999

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E2F-1, a transcription factor implicated in the activation of genes required for S phase such as DNA pol a, is regulated by interactions with Rb and by cell-cycle dependent alterations in E2F-1 abundance. We have shown that depletion of poly(ADP-ribose) polymerase (PARP) by antisense RNA expression downregulates pol a and E2F-1 expression during early S phase. To examine the role of PARP in the regulation of pol a and E2F-1 gene expression, we utilized immortalized mouse ®broblasts derived from wild-type and PARP knockout (PARP7/7) mice as well as PARP7/7 cells stably transfected with PARP cDNA [PARP7/7(+PARP)]. After release from serum deprivation, wild-type and PARP7/7(+PARP) cells, but not PARP7/7 cells, exhibited a peak of cells in S phase by 16 h and had progressed through the cell cycle by 22 h. Whereas [ 3 H]thymidine incorporation remained negligible in PARP7/7 cells, in vivo DNA replication maximized after 18 h in wild-type and PARP7/7(+PARP) cells. To investigate the e ect of PARP on E2F-1 promoter activity, a construct containing the E2F-1 gene promoter fused to a luciferase reporter gene was transiently transfected into these cells. E2F-1 promoter activity in control and PARP7/7(+PARP) cells increased eightfold after 9 h, but not in PARP7/7 cells. PARP7/7 cells did not show the marked induction of E2F-1 expression during early S phase apparent in control and PARP7/7(+PARP) cells. RT ± PCR analysis and pol a activity assays revealed the presence of pol a transcripts and a sixfold increase in activity in both wildtype and PARP7/7(+PARP) cells after 20 h, but not in PARP7/7 cells. These results suggest that PARP plays a role in the induction of E2F-1 promoter activity, which then positively regulates both E2F-1 and pol a expression, when quiescent cells reenter the cell cycle upon recovery from aphidicolin exposure or removal of serum.

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Section: Discussionmentioning

confidence: 99%

Section: Parp7/7 Cells Do Not Show the Marked Induction Of E2f-1 Exprmentioning

confidence: 99%

Poly(ADP-ribose) polymerase upregulates E2F-1 promoter activity and DNA pol α expression during early S phase

et al. 1999

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“…Moreover, ETS motifs are frequently located in the vicinity of the transcription start site in a number of promoters that lack a TATA element, including the genes encoding DNA polymerase a and b (Pearson et al, 1991;Yamaguchi et al, 1988), thymidilate synthetase (Jolli and Johnson, 1991), von Willebrand factor (Schwachtgen et al, 1998), Ets2 (Mavrothalassitis et al, 1990, the tumor suppressor gene Maspin (Zhang et al, 1997) and number of myeloid speci®c genes (reviewed by Moreau-Gachelin, 1994). It seems that PARP can be added to this group of genes because it exhibits features typical of TATA-de®cient promoters and has consensus ETS motifs close to the major initiation sites.…”

Section: Inhibition Of Ets1 Expression Enhances Growth Retardation Ofmentioning

confidence: 99%

Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor

et al. 1999

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Ewing's sarcoma (EWS) cells accumulate elevated steady-state levels of poly (ADP-ribose) polymerase (PARP) mRNA and protein. To understand the molecular mechanisms underlying PARP upregulation, we cloned and analysed the 5'-¯anking region of the PARP gene from EWS cells. Nucleotide sequence analysis demonstrated no variations in the PARP promoter region in EWS cells. The PARP promoter encompasses multiple binding motifs for the ETS transcription factor. We have also observed that there is a coordinated up-regulation of the expression of both PARP and ETS1, relative to cells of other human tumor types expressing lower levels of PARP. Transient coexpression of ETS1 in EWS cells resulted in a strong enhancement of PARP-promoter activity. The participation of ETS in the regulation of PARP gene expression was further demonstrated in EWS cells stably transfected with Ets1 antisense cDNA constructs. Antisensemediated down-regulation of endogenous ETS1 resulted in the inhibition of PARP expression in EWS cells, and sensitized these cells to ionizing radiation. These data provide support for ETS regulation of PARP expression levels, and implicate ETS transcription factors in the radiation response of EWS cells.

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“…While E2F forms a complex with cyclin A and cdk 2, the major component of the complex during the early part of the cell cycle is the retinoblastoma protein (Rb). [22][23][24] As the cells enter S-phase, Rb is phosphorylated and leaves the complex, allowing E2F to induce cell cycle regulatory genes including c-myc, cmyb, cdc2, proliferating cell nuclear antigen (PCNA) and thymidine kinase, [25][26][27][28][29] resulting in the initiation of cell proliferation. Thus, we also hypothesize that transfection of tumor with sufficient quantities of the decoy ODN containing the E2F binding site would effectively bind E2F, and prevent it from transactivating the expression of cell cycle regulatory genes ( Figure 1) and thereby inhibit tumor growth in vivo.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Kawamura¹,

et al. 1999

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Cancer cachexia, characterized by anorexia, weight loss muscle mass and food intake, which were induced by the and progressive tissue wasting, has been postulated to be tumor presence. Interleukin 6 mRNA in the tumor was also mediated by various cytokines. However, the precise markedly decreased by the transfection of NF B decoy mechanism of cachexia induction is not fully explained. We ODN. It is known that the transcriptional factor E2F plays have developed synthetic double-stranded oligodeoxynua pivotal role in the coordinated transactivation of cell cycle cleotides (ODN) as 'decoy' cis-elements that block the regulatory genes. Therefore, we hypothesized that the binding of nuclear factors to promoter regions of targeted introduction of synthetic double-stranded DNA with high genes, resulting in the inhibition of gene transactivation in affinity for E2F in vivo as 'decoy' cis-elements might inhibit vivo as well as in vitro. This novel molecular strategy could the tumor growth of colon26, resulting in turn in inhibition of be useful for treating a broad range of human diseases cachexia induction. However, injection of E2F decoy ODN including cancer. In this study, we injected decoy ODN tarfailed to inhibit tumor growth and cachexia induction, as geting the transcriptional factor, NF-kappaB (NF B) bindcompared with mismatched decoy ODN. Overall, the ing cis-elements, which are essential for transactivation of present study demonstrated that cachexia induced by gene expression of cytokines, directly into tumors of adenocarcinoma colon26 was inhibited by blocking of adenocarcinoma colon26 in mice, in order to examine NF B, using a novel molecular decoy strategy, without an whether or not cachexia is alleviated by inhibiting the action effect on tumor growth, and also that tumor growth and of cytokines. Tumor growth was not affected by transfeccachexia induction in the colon26 model were not affected tion of NF B decoy ODN as compared with scrambled by E2F decoy ODN. These results suggest that cytokines decoy ODN. Nevertheless, transfection of NF B decoy, but regulated by NF B may play a pivotal role in the induction not scrambled decoy, ODN resulted in attenuation of the of cachexia by colon26, providing a new therapeutic reductions in body weight, epididymal fat, gastrocnemius strategy for cancer cachexia.

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Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells.

Cited by 212 publications

References 61 publications

Poly(ADP-ribose) polymerase upregulates E2F-1 promoter activity and DNA pol α expression during early S phase

Poly(ADP-ribose) polymerase upregulates E2F-1 promoter activity and DNA pol α expression during early S phase

Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

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