Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation

BackgroundInsulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.MethodsIn this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.ResultsDeletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated.ConclusionFrom these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.

• Publication year

  2005

• Venue

  BMC Cancer

• Publication date

  2005-01-20

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/1471-2407-5-9PMID 15661074PMCID 548269
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer

  2004cited by this paper
• Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer.

  2004cited by this paper
• A Mouse Skin Multistage Carcinogenesis Model Reflects the Aberrant DNA Methylation Patterns of Human Tumors

  2004cited by this paper
• Overexpression of KIT in chromophobe renal cell carcinoma

  2003cited by this paper
• Insulin-like Growth Factor (IGF)-binding Protein-3 Mutants That Do Not Bind IGF-I or IGF-II Stimulate Apoptosis in Human Prostate Cancer Cells*

  2002cited by this paper
• Signaling through the Smad Pathway by Insulin-like Growth Factor-binding Protein-3 in Breast Cancer Cells

  2002cited by this paper
• Gene expression correlates of clinical prostate cancer behavior.

  2002cited by this paper
• A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation.

  2002cited by this paper
• Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3.

  2002cited by this paper
• Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma.

  2002cited by this paper
• Butyrate, a histone deacetylase inhibitor, activates the human IGF binding protein-3 promoter in breast cancer cells: molecular mechanism involves an Sp1/Sp3 multiprotein complex.

  2001cited by this paper
• Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators.

  2001cited by this paper
• Human Papillomavirus Type 16 E7 Oncoprotein Binds and Inactivates Growth-Inhibitory Insulin-Like Growth Factor Binding Protein 3

  2000cited by this paper
• Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver.

  2000cited by this paper
• Growth inhibition by insulin-like growth factor-binding protein-3 in T47D breast cancer cells requires transforming growth factor-beta (TGF-beta ) and the type II TGF-beta receptor.

  2000cited by this paper
• Growth Inhibition by Insulin-like Growth Factor-binding Protein-3 in T47D Breast Cancer Cells Requires Transforming Growth Factor-β (TGF-β) and the Type II TGF-β Receptor*

  2000cited by this paper
• Down‐regulation of insulin‐like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid

  1999cited by this paper
• Sequence alterations of insulin-like growth factor binding protein 3 in neoplastic and normal gastrointestinal tissues.

  1998cited by this paper
• Further characterisation of the p53 responsive element – identification of new candidate genes for trans-activation by p53

  1997cited by this paper
• Insulin-like growth factor binding proteins and their role in controlling IGF actions.

  1997influential reference
• Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism*

  1997cited by this paper
• Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features.

  1996cited by this paper
• Insulin-like Growth Factor Binding Protein 3 Mediates Retinoic Acid- and Transforming Growth Factor β2-induced Growth Inhibition in Human Breast Cancer Cells

  1996cited by this paper
• Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells.

  1996cited by this paper
• A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis

  1996cited by this paper
• Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function

  1996cited by this paper
• Tumor necrosis factor alpha stimulates insulin-like growth factor binding protein 3 expression in cultured porcine Sertoli cells.

  1996cited by this paper
• Induction of the growth inhibitor IGF-binding protein 3 by p53

  1995cited by this paper
• Insulin-Like Growth Factor Binding Protein-3

  1994cited by this paper
• Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation

  1990cited by this paper
• Insulin-like growth factor binding protein-3. Organization of the human chromosomal gene and demonstration of promoter activity.

  1990cited by this paper

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  2026cites this paper
• IGFBP3 modulation of tumor pathogenesis and cell signaling pathways (Review)

  2025cites this paper
• Role of Insulin-like Growth Factor-1 Receptor in Tobacco Smoking-Associated Lung Cancer Development

  2024cites this paper
• The Interplay Between Non-coding RNAs and Insulin-Like Growth Factor Signaling in the Pathogenesis of Neoplasia

  2021cites this paper
• Epigenetics in hepatoblastoma

  2021cites this paper
• Disorders of Keratinization

  2021cites this paper
• IGFBP3 inhibits angiogenesis through intracellular regulation of THBS1 expression.

  2020cites this paper
• Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

  2020cites this paper
• The insulin‐like growth factor binding protein‐3 and its death receptor in pancreatic ductal adenocarcinoma poor prognosis

  2019cites this paper
• Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer

  2016cites this paper
• The role of NFE2L2 mutations and the epigenetic regulator UHRF1 in hepatoblastoma

  2016cites this paper
• Effect of Environmental Chemical Exposures on Epigenetics of Diseases: A Systematic Review

  2016influential citation
• Nuclear actions of insulin-like growth factor binding protein-3.

  2015cites this paper
• Insulin-like growth factor binding protein-3 mediates interleukin-24-induced apoptosis through inhibition of the mTOR pathway in prostate cancer

  2015cites this paper
• Spontaneous Transformation of Murine Oviductal Epithelial Cells: A Model System to Investigate the Onset of Fallopian-Derived Tumors

  2015cites this paper
• Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer

  2015cites this paper
• Comparison of Lymphedema Incidence Between 2 Lymphadenectomy Techniques in Patients With Uterine Cancer Undergoing Robotic Staging

  2015cites this paper
• Involvement of the insulin-like growth factor binding proteins in the cancer cell response to DNA damage

  2015cites this paper
• CUL4B promotes proliferation and inhibits apoptosis of human osteosarcoma cells.

  2014cites this paper
• Patró de metilació d'un panell de biomarcadors en l'adenocarcinoma pulmonar

  2013influential citation
• CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing

  2013cites this paper
• Environmental chemical exposures and human epigenetics.

  2012cites this paper
• Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents

  2012cites this paper
• Insulin‐like growth factor receptor expression is associated with aggressive phenotypes and has therapeutic activity in biliary tract cancers

  2012cites this paper
• Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF‐1α‐mediated mRNA transcription and continuous protein synthesis

  2012cites this paper
• MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer.

  2011cites this paper
• Involvement of Insulin-like Growth Factor-binding Protein-3 in the Effects of Histone Deacetylase Inhibitor MS-275 in Hepatoma Cells

  2011cites this paper
• IGF-I and IGFBP-3 before and after inpatient alcohol detoxification in alcohol-dependent subjects

  2011cites this paper
• Viral Hepatitis B

  2011cites this paper
• Insulin-like growth factor binding protein-3 gene methylation and protein expression in gastric adenocarcinoma.

  2010cites this paper
• Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma

  2009influential citation
• Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age.

  2009cites this paper
• Local IGFBP-3 mRNA expression, apoptosis and risk of colorectal adenomas

  2008cites this paper
• IGFBP-3 mediates the effect of tumor suppressor NKX3.1 on prostate cancer cell proliferation

  2008cites this paper
• Identification of upstream stimulatory factor binding sites in the human IGFBP3 promoter and potential implication of adjacent single-nucleotide polymorphisms and responsiveness to insulin.

  2007cites this paper
• Aberrant promoter methylation of insulin‐like growth factor binding protein‐3 gene in human cancers

  2007influential citation
• Adalimumab: in Crohn's disease.

  2007cites this paper
• Molecular Pathogenesis of Hepatitis-B-virus-associated Hepatocellular Carcinoma.

  2007cites this paper
• Mitochondrial membrane permeabilization in cell death.

  2007cites this paper
• In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

  2007cites this paper
• IGFBP3 promoter methylation in colorectal cancer: relationship with microsatellite instability, CpG island methylator phenotype, and p53.

  2007cites this paper
• IGFBP3 Promoter Methylation in Colorectal Cancer: Relationship with Microsatellite Instability, CpG Island Methylator Phenotype, p53

  2007cites this paper
• Identification of USF Binding Sites in the Human IGFBP3 Promoter and Potential Implication of Adjacent Single Nucleotide Polymorphisms and Responsiveness to Insulin

  2007cites this paper
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  2007cites this paper
• Chronic hepatitis B in hepatocarcinogenesis

  2006cites this paper
• Regularly methylated novel pro‐apoptotic genes associated with recurrence in transitional cell carcinoma of the bladder

  2006cites this paper
• Molekulare Wirkungsmechanismen von n-Butyrat

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  2006cites this paper
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  2006cites this paper
• Insulin-like growth factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling

  2006cites this paper
• IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways.

  2005cites this paper
• p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia.

  2005cites this paper