Functional Promoter Upstream P53 Regulatory Sequence of IGFBP3 That is Silenced by Tumor Specific Methylation

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2005 Jan 22

PMID 15661074

Citations 25

Authors

Tadashi Hanafusa

Toshiyuki Shinji

Hidenori Shiraha

Kazuhiro Nouso

Yoshiaki Iwasaki

Eichiro Yumoto

Toshiro Ono

Norio Koide

Affiliations

Soon will be listed here.

Abstract

Background: Insulin-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.

Methods: In 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.

Results: Deletions 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.

Conclusion: From 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.

Citing Articles

Role of Insulin-like Growth Factor-1 Receptor in Tobacco Smoking-Associated Lung Cancer Development.

Shahid A, Santos S, Lin C, Huang Y Biomedicines. 2024; 12(3).

PMID: 38540176 PMC: 10967781. DOI: 10.3390/biomedicines12030563.

The Interplay Between Non-coding RNAs and Insulin-Like Growth Factor Signaling in the Pathogenesis of Neoplasia.

Ghafouri-Fard S, Abak A, Mohaqiq M, Shoorei H, Taheri M Front Cell Dev Biol. 2021; 9:634512.

PMID: 33768092 PMC: 7985092. DOI: 10.3389/fcell.2021.634512.

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications.

Saik O, Klimontov V Int J Mol Sci. 2020; 21(22).

PMID: 33217980 PMC: 7698756. DOI: 10.3390/ijms21228691.

IGFBP3 inhibits angiogenesis through intracellular regulation of THBS1 expression.

Shih H, Chen C, Torng P Am J Cancer Res. 2020; 10(6):1728-1744.

PMID: 32642286 PMC: 7339270.

Oncogenic function of the homeobox A13-long noncoding RNA HOTTIP-insulin growth factor-binding protein 3 axis in human gastric cancer.

Wang S, Wuputra K, Liu C, Lin Y, Chen Y, Chai C Oncotarget. 2016; 7(24):36049-36064.

PMID: 27144338 PMC: 5094982. DOI: 10.18632/oncotarget.9102.

References

Zimmermann E, Li L, Hoyt E, Pucilowska J, Lichtman S, Lund P . Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver. Am J Physiol Gastrointest Liver Physiol. 2000; 278(3):G447-57. DOI: 10.1152/ajpgi.2000.278.3.G447. View

Huynh H, Chow P, Ooi L, Soo K . A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ. 2002; 13(3):115-22. View

Fanayan S, Firth S, BUTT A, BAXTER R . 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. J Biol Chem. 2000; 275(50):39146-51. DOI: 10.1074/jbc.M006964200. View

Deal C, Ma J, Wilkin F, Paquette J, ROZEN F, Ge B . Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab. 2001; 86(3):1274-80. DOI: 10.1210/jcem.86.3.7280. View

Walker G, Wilson E, Powell D, Oh Y . 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. Endocrinology. 2001; 142(9):3817-27. DOI: 10.1210/endo.142.9.8380. View

Hanafusa T, Yumoto Y, Nouso K, Nakatsukasa H, Onishi T, Fujikawa T . Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma. Cancer Lett. 2002; 176(2):149-58. DOI: 10.1016/s0304-3835(01)00736-4. View

Singh D, Febbo P, Ross K, Jackson D, Manola J, Ladd C . Gene expression correlates of clinical prostate cancer behavior. Cancer Cell. 2002; 1(2):203-9. DOI: 10.1016/s1535-6108(02)00030-2. View

Lee K, Cohen P . Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3. J Endocrinol. 2002; 175(1):33-40. DOI: 10.1677/joe.0.1750033. View

Yamazaki K, Sakamoto M, Ohta T, Kanai Y, Ohki M, Hirohashi S . Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene. 2003; 22(6):847-52. DOI: 10.1038/sj.onc.1206153. View

10.

Kettunen E, Anttila S, Seppanen J, Karjalainen A, Edgren H, Lindstrom I . Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer. Cancer Genet Cytogenet. 2004; 149(2):98-106. DOI: 10.1016/S0165-4608(03)00300-5. View

11.

Fraga M, Herranz M, Espada J, Ballestar E, Paz M, Ropero S . A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 2004; 64(16):5527-34. DOI: 10.1158/0008-5472.CAN-03-4061. View

12.

Chang Y, Wang L, Suh Y, Mao L, Karpen S, Khuri F . Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer. Oncogene. 2004; 23(39):6569-80. DOI: 10.1038/sj.onc.1207882. View

13.

Laiho M, DeCaprio J, Ludlow J, Livingston D, Massague J . Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990; 62(1):175-85. DOI: 10.1016/0092-8674(90)90251-9. View

14.

Cubbage M, Suwanichkul A, Powell D . Insulin-like growth factor binding protein-3. Organization of the human chromosomal gene and demonstration of promoter activity. J Biol Chem. 1990; 265(21):12642-9. View

15.

Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger B . Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 1995; 377(6550):646-9. DOI: 10.1038/377646a0. View

16.

Besset V, Le Magueresse-Battistoni B, Collette J, Benahmed M . Tumor necrosis factor alpha stimulates insulin-like growth factor binding protein 3 expression in cultured porcine Sertoli cells. Endocrinology. 1996; 137(1):296-303. DOI: 10.1210/endo.137.1.8536626. View

17.

Gucev Z, Oh Y, Kelley K, Rosenfeld R . Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells. Cancer Res. 1996; 56(7):1545-50. View

18.

Rocha R, Hilsenbeck S, Jackson J, Lee A, Figueroa J, Yee D . 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. J Natl Cancer Inst. 1996; 88(9):601-6. DOI: 10.1093/jnci/88.9.601. View

19.

Ludwig R, Bates S, Vousden K . Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol. 1996; 16(9):4952-60. PMC: 231497. DOI: 10.1128/MCB.16.9.4952. View

20.

Friedlander P, Haupt Y, Prives C, Oren M . A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol Cell Biol. 1996; 16(9):4961-71. PMC: 231498. DOI: 10.1128/MCB.16.9.4961. View