Kinetic analysis of Sp1-mediated transcriptional activation of the human DNA polymerase β promoter

Narayan, Satya; Wilson, Samuel H.

doi:10.1038/sj.onc.1203823

Cited by 18 publications

(7 citation statements)

References 45 publications

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“…Wilson et al further identified SP1 and CRE sites within this region [23]. Sp1 sites in the human core β-POL promoter have been shown to be involved in the transcriptional activation of the TATA less promoter [49]. The CRE site, the general binding site for ATF-1, CREB-1, CREM-1 and AP-1, has been shown to be involved in the expression of human β-POL during basal conditions and during stress [24–26,50].…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress

Unnikrishnan

Prychitko

Patel

et al. 2011

Free Radical Biology and Medicine

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Folate deficiency has been shown to influence carcinogenesis by creating an imbalance in the base excision repair (BER) pathway impacting BER homeostasis. The inability to mount a BER response to oxidative stress in a folate deficient environment results in the accumulation of DNA repair intermediates, i.e., DNA strand breaks. Our data indicate that upregulation in β-pol expression in response to oxidative stress is inhibited by folate deficiency at the level of gene expression. Alteration in expression of β-pol in a folate deficient environment is not due to epigenetic changes in the core promoter of the β-pol gene, i.e., the CpG islands within the β-pol promoter remain unmethylated in the presence and/or absence of folate. However, the promoter analysis studies show a differential binding of regulatory factor(s) to the −36 to −7 region (the folic acid response region, FARR) within the core promoter of β-pol. Moreover, we observe a tight correlation between the level of binding of regulatory factor(s) with the FARR and inhibition of β-pol expression. Based on these findings, we propose that folate deficiency results in an upregulation/stability of negative regulatory factor(s) interacting with FARR, repressing the upregulation of the β-pol gene in response to oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress

Unnikrishnan

Prychitko

Patel

et al. 2011

Free Radical Biology and Medicine

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“…This upregulation requires the presence of the specific cAMP response element (CRE) in the promoter of the Pol β gene (9,10). It has also been shown that the Pol β promoter contains a binding site for the transcription factor SP1 (11). Although regulation at the transcription level is apparent, expression of the Pol β transcripts might also be controlled at the post-transcriptional level.…”

Section: Introductionmentioning

confidence: 99%

Hairpin structure within the 3'UTR of DNA polymerase mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1

Sarnowska

Grzybowska

Sobczak

et al. 2007

Nucleic Acids Research

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Aberrant expression of DNA polymerase β, a key enzyme involved in base excision repair, leads to genetic instability and carcinogenesis. Pol β expression has been previously shown to be regulated at the level of transcription, but there is also evidence of post-transcriptional regulation, since rat transcripts undergo alternative polyadenylation, and the resulting 3′UTR contain at least one regulatory element. Data presented here indicate that RNA of the short 3′UTR folds to form a strong secondary structure (hairpin). Its regulatory role was established utilizing a luciferase-based reporter system. Further studies led to the identification of a protein factor, which binds to this element—the anti-apoptotic, cytoskeleton-related protein Hax-1. The results of in vitro binding analysis indicate that the formation of the RNA–protein complex is significantly impaired by disruption of the hairpin motif. We demonstrate that Hax-1 binds to Pol β mRNA exclusively in the form of a dimer. Biochemical analysis revealed the presence of Hax-1 in mitochondria, but also in the nuclear matrix, which, along with its transcript-binding properties, suggests that Hax-1 plays a role in post-transcriptional regulation of expression of Pol β.

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“…TEL is one of a subset of the ETS family of transcription factors that contains a conserved N‐terminal domain which has been variously referred to as the pointed (PNT) domain, based on homology to the Drosophila ETS‐protein pointed , the N‐terminal conserved domain (NCR), or the helix‐loop‐helix domain, based on weak homology to the basic helix‐loop‐helix domain found in transcription factors such as myc and myo‐D (Wasylyk et al ., 1993). The PNT domain was shown to be important for transcriptional activity despite the lack of DNA contact, but no other function was known prior to the cloning of the TEL/PDGFRβ fusion gene (Rao et al ., 1993). Analysis of the TEL fusion proteins in the context of the PNT domain has provided evidence that this domain acts as a self association domain of functional importance.…”

Section: Introductionmentioning

confidence: 99%

Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes

Schwaller

Frantsve

Aster

et al. 1998

EMBO J

243

260

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Recent reports have demonstrated fusion of the TEL gene on 12p13 to the JAK2 gene on 9p24 in human leukemias. Three variants have been identified that fuse the TEL pointed (PNT) domain to (i) the JAK2 JH1-kinase domain, (ii) part of and (iii) all of the JH2 pseudokinase domain. We report that all of the human TEL/JAK2 variants, and a human/mouse chimeric hTEL/mJAK2(JH1) fusion gene, transform the interleukin-3 (IL-3)-dependent murine hematopoietic cell line Ba/F3 to IL-3-independent growth. Transformation requires both the TEL PNT domain and JAK2 kinase activity. Furthermore, all TEL/JAK2 variants strongly activated STAT 5 by phosphotyrosine Western blots and by electrophoretic mobility shift assays (EMSA). Mice (n = 40) transplanted with bone marrow infected with the MSCV retrovirus containing either the hTEL/mJAK2(JH1) fusion or its human counterpart developed a fatal mixed myeloproliferative and T-cell lymphoproliferative disorder with a latency of 2-10 weeks. In contrast, mice transplanted with a TEL/JAK2 mutant lacking the TEL PNT domain (n = 10) or a kinase-inactive TEL/JAK2(JH1) mutant (n = 10) did not develop the disease. We conclude that all human TEL/JAK2 fusion variants are oncoproteins in vitro that strongly activate STAT 5, and cause lethal myelo- and lymphoproliferative syndromes in murine bone marrow transplant models of leukemia.

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Kinetic analysis of Sp1-mediated transcriptional activation of the human DNA polymerase β promoter

Cited by 18 publications

References 45 publications

Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress

Folate deficiency regulates expression of DNA polymerase β in response to oxidative stress

Hairpin structure within the 3'UTR of DNA polymerase mRNA acts as a post-transcriptional regulatory element and interacts with Hax-1

Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes

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