Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression

Fujimoto, Masayo; Kitazawa, Riko; Maeda, Sakan; Kitazawa, Sohei

doi:10.1038/sj.onc.1208697

Cited by 28 publications

(19 citation statements)

References 36 publications

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“…In previous study, AP1-like binding site (TGAGCGA) was identified as a methylated insulator region in human blastoma cell line [31]. Analyzed region in front of porcine OPN promoter showed that CpG 1st binding site contained the specific binding site sequence.…”

Section: Discussionmentioning

confidence: 99%

Osteoponin Promoter Controlled by DNA Methylation: Aberrant Methylation in Cloned Porcine Genome

Shen

Tsou

Chen

et al. 2014

BioMed Research International

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Cloned animals usually exhibited many defects in physical characteristics or aberrant epigenetic reprogramming, especially in some important organ development. Osteoponin (OPN) is an extracellular-matrix protein involved in heart and bone development and diseases. In this study, we investigated the correlation between OPN mRNA and its promoter methylation changes by the 5-aza-dc treatment in fibroblast cell and promoter assay. Aberrant methylation of porcine OPN was frequently found in different tissues of somatic nuclear transferred cloning pigs, and bisulfite sequence data suggested that the OPN promoter region −2615 to −2239 nucleotides (nt) may be a crucial regulation DNA element. In pig ear fibroblast cell culture study, the demethylation of OPN promoter was found in dose-dependent response of 5-aza-dc treatment and followed the OPN mRNA reexpression. In cloned pig study, discrepant expression pattern was identified in several cloned pig tissues, especially in brain, heart, and ear. Promoter assay data revealed that four methylated CpG sites presenting in the −2615 to −2239 nt region cause significant downregulation of OPN promoter activity. These data suggested that methylation in the OPN promoter plays a crucial role in the regulation of OPN expression that we found in cloned pigs genome.

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Section: Discussionmentioning

confidence: 99%

Osteoponin Promoter Controlled by DNA Methylation: Aberrant Methylation in Cloned Porcine Genome

Shen

Tsou

Chen

et al. 2014

BioMed Research International

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“…Although transcriptional regulation by DNA methylation is often observed in CpG islands located around the promoter region via the sequence-nonspecific and methylation-specific binding of inhibiting methylated CpG-binding proteins [38, 41], DNA methylation of sequence-specific transcription factor binding sites can alter gene expression through changes in the binding affinity of transcription factors by altering the major groove structure of DNA to which the DNA-binding proteins bind [42–44]. The finding that the Sp1 probes with methylated CpG dinucleotides at the core of the consensus Sp1 elements in the Prkce promoter abolished the binding of SP1 indicates that CpG methylation in non-CpG islands and sequence-specific Sp1 binding sites can directly inhibit the DNA binding of SP1, resulting in down-regulation of Prkce gene expression in the heart.…”

Section: Discussionmentioning

confidence: 99%

Fetal Exposure to Cocaine Causes Programming of Prkce Gene Repression in the Left Ventricle of Adult Rat Offspring1

Zhang

Meyer

Zhang

2009

Biology of Reproduction

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Previous studies demonstrated that maternal cocaine administration caused a significant decrease in protein kinase C epsilon (PRKCE) abundance in the left ventricle and an increase in susceptibility of the heart to ischemic injury in adult male offspring. The present study tested the hypothesis that epigenetic modification has a key role in cocaine-mediated programming of cardiac Prkce gene repression. Pregnant Sprague-Dawley rats were administered saline or cocaine (30 mg/kg/day i.p.) from Days 15 to 21 of gestational age, and hearts of 3-mo-old adult offspring were studied. Cocaine exposure significantly decreased Prkce mRNA levels in the left ventricle of male but not female offspring. CpG dinucleotides identified in Bhlhb2, Pparg, E2f, and Egr1 binding sites at the Prkce gene promoter were densely methylated in males and females and were unaffected by cocaine exposure. In contrast, methylation of CpGs in the two Sp1 binding sites (−346 and −268) was low and was significantly increased by cocaine exposure in male offspring. In females, methylation of the Sp1 binding site at −268 but not −346 was increased. Reporter gene assays showed that both Sp1 binding sites had a strong stimulatory role in Prkce gene activity. Methylation of the Sp1 binding sites significantly decreased SP1 binding to the Prkce promoter. Cocaine exposure did not affect nuclear SP1 protein levels but decreased the SP1 binding affinity to its binding site at −268. The results demonstrate an epigenetic mechanism of DNA methylation in programming of cardiac Prkce gene repression, linking fetal cocaine exposure and pathophysiological consequences in the heart of adult male offspring in a gender-dependent manner.

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“…Aberrant or increased TrkA expression has also been reported in human nonneural tumors including prostate, breast, lung, and pancreatic cancers [53]. A negative cis-acting AP1-like sequence, TGAGCGA, was found in the 5'-untranslated region of the human TrkA gene [53]. This AP1-like site was bound mainly by c-Jun homodimers and the binding was directly blocked by methylation.…”

Section: Trka Transcriptional Regulationmentioning

confidence: 95%

“…Similarly, a 138-bp region located just upstream of the transcription initiation site of the human TrkA gene was also shown to be important for transcription of TrkA in neuroblastoma cell lines [52]. Aberrant or increased TrkA expression has also been reported in human nonneural tumors including prostate, breast, lung, and pancreatic cancers [53]. A negative cis-acting AP1-like sequence, TGAGCGA, was found in the 5'-untranslated region of the human TrkA gene [53].…”

Section: Trka Transcriptional Regulationmentioning

confidence: 96%

Transcriptional regulation of Trk family neurotrophin receptors

Parada

2006

Cell. Mol. Life Sci.

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The Trk family of neurotrophin receptors plays essential roles in cell fate specification, survival, growth, and differentiation. Their expression patterns are complex and dynamically regulated under many physiological and pathological conditions. However, the molecular mechanisms that control their tissue-specific expression are largely unknown. In this report, we review current knowledge about the transcriptional regulation of Trk receptors.

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Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression

Cited by 28 publications

References 36 publications

Osteoponin Promoter Controlled by DNA Methylation: Aberrant Methylation in Cloned Porcine Genome

Osteoponin Promoter Controlled by DNA Methylation: Aberrant Methylation in Cloned Porcine Genome

Fetal Exposure to Cocaine Causes Programming of Prkce Gene Repression in the Left Ventricle of Adult Rat Offspring1

Transcriptional regulation of Trk family neurotrophin receptors

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