Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

A Functional SNP in the MDM2 Promoter Mediates E2F1 Affinity to Modulate Cyclin D1 Expression in Tumor Cell Proliferation

  • Yang, Zhen-Hai (Department of Dermatology, No.1 Hospital of China Medical University) ;
  • Zhou, Chun-Lin (Department of Dermatology, No.1 Hospital of China Medical University) ;
  • Zhu, Hong (Department of Dermatology, No.1 Hospital of China Medical University) ;
  • Li, Jiu-Hong (Department of Dermatology, No.1 Hospital of China Medical University) ;
  • He, Chun-Di (Department of Dermatology, No.1 Hospital of China Medical University)
  • Published : 2014.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: The MDM2 oncogene, a negative regulator of p53, has a functional polymorphism in the promoter region (SNP309) that is associated with multiple kinds of cancers including non-melanoma skin cancer. SNP309 has been shown to associate with accelerated tumor formation by increasing the affinity of the transcriptional activator Sp1. It remains unknown whether there are other factors involved in the regulation of MDM2 transcription through a trans-regulatory mechanism. Methods: In this study, SNP309 was verified to be associated with overexpression of MDM2 in tumor cells. Bioinformatics predicts that the T to G substitution at SNP309 generates a stronger E2F1 binding site, which was confirmed by ChIP and luciferase assays. Results: E2F1 knockdown downregulates the expression of MDM2, which confirms that E2F1 is a functional upstream regulator. Furthermore, tumor cells with the GG genotype exhibited a higher proliferation rate than TT, correlating with cyclin D1 expression. E2F1 depletion significantly inhibits the proliferation capacity and downregulates cyclin D1 expression, especially in GG genotype skin fibroblasts. Notably, E2F1 siRNA effects could be rescued by cyclin D1 overexpression. Conclusion: Taken together, a novel modulator E2F1 was identified as regulating MDM2 expression dependent on SNP309 and further mediates cyclin D1 expression and tumor cell proliferation. E2F1 might act as an important factor for SNP309 serving as a rate-limiting event in carcinogenesis.

Keywords

References

  1. Almquist LM, Karagas MR, Christensen BC et al (2011). The role of TP53 and MDM2 polymorphisms in TP53 mutagenesis and risk of non-melanoma skin cancer. Carcinogenesis, 32, 327-30. https://doi.org/10.1093/carcin/bgq256
  2. Ambrosini G, Sambol EB, Carvajal D et al (2007). Mouse double minute antagonist Nutlin-3a enhances chemotherapyinduced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene, 26, 3473-81. https://doi.org/10.1038/sj.onc.1210136
  3. Azmi AS, Philip PA, Aboukameel A et al (2010). Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy. Curr Cancer Drug Targets, 10, 319-31. https://doi.org/10.2174/156800910791190229
  4. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993). Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev, 7, 812-21. https://doi.org/10.1101/gad.7.5.812
  5. Blaydes JP, Wynford-Thomas D (1998). The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2. Oncogene, 16, 3317-22. https://doi.org/10.1038/sj.onc.1201880
  6. Bond GL, Hu W, Bond EE et al (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell, 119, 591-602. https://doi.org/10.1016/j.cell.2004.11.022
  7. Burton EC, Lamborn KR, Forsyth P et al (2002). Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res, 8, 180-7.
  8. Chen H, Zhang D, Wu J et al (2014). Ubiquitination of p53 is involved in troglitazone induced apoptosis in cervical cancer cells. Asian Pac J Cancer Prev, 15, 2313-8. https://doi.org/10.7314/APJCP.2014.15.5.2313
  9. Cheng H, Ma B, Jiang R et al (2012). Individual and combined effects of MDM2 SNP309 and TP53 Arg72Pro on breast cancer risk: an updated meta-analysis. Mol Biol Rep, 39, 9265-74. https://doi.org/10.1007/s11033-012-1800-z
  10. Del SG, Murphy M, Ruaro E et al (1996). Cyclin D1 and p21/waf1 are both involved in p53 growth suppression. Oncogene, 12, 177-85.
  11. Dharel N, Kato N, Muroyama R et al (2006). MDM2 promoter SNP309 is associated with the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Clin Cancer Res, 12, 4867-71. https://doi.org/10.1158/1078-0432.CCR-06-0111
  12. Dong HJ, Fang C, Fan L et al (2012). MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL. Int J Cancer, 130, 2054-61. https://doi.org/10.1002/ijc.26222
  13. Evan GI, Vousden KH (2001). Proliferation, cell cycle and apoptosis in cancer. Nature, 411, 342-8. https://doi.org/10.1038/35077213
  14. Fearon ER (1997). Human cancer syndromes: clues to the origin and nature of cancer. Science, 278, 1043-50. https://doi.org/10.1126/science.278.5340.1043
  15. Francoz S, Froment P, Bogaerts S et al (2006). Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci USA, 103, 3232-7. https://doi.org/10.1073/pnas.0508476103
  16. Frazer KA, Murray SS, Schork NJ, Topol EJ (2009). Human genetic variation and its contribution to complex traits. Nat Rev Genet, 10, 241-51.
  17. Frietze S, Lupien M, Silver PA, Brown M (2008). CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res, 68, 301-6. https://doi.org/10.1158/0008-5472.CAN-07-1983
  18. Grinstein E, Jundt F, Weinert I, Wernet P, Royer HD (2002). Sp1 as G1 cell cycle phase specific transcription factor in epithelial cells. Oncogene, 21, 1485-92. https://doi.org/10.1038/sj.onc.1205211
  19. Guan Y, Yang X, Yao G et al (2014). Breast cancer association studies in a Han Chinese population using 10 Europeanancestry-associated breast cancer susceptibility SNPs. Asian Pac J Cancer Prev, 15, 85-91. https://doi.org/10.7314/APJCP.2014.15.1.85
  20. Hitzenbichler F, Stoehr CG, Rogenhofer M et al (2013). Mdm2 SNP309 G-variant is associated with invasive growth of human urinary bladder cancer. Pathobiology, 81, 53-9.
  21. Hori M, Shimazaki J, Inagawa S, Itabashi M, Hori M (2002). Overexpression of MDM2 oncoprotein correlates with possession of estrogen receptor alpha and lack of MDM2 mRNA splice variants in human breast cancer. Breast Cancer Res Treat, 71, 77-83. https://doi.org/10.1023/A:1013350419426
  22. Hu Z, Jin G, Wang L, Chen F, Wang X, Shen H (2007). MDM2 promoter polymorphism SNP309 contributes to tumor susceptibility: evidence from 21 case-control studies. Cancer Epidemiol Biomarkers Prev, 16, 2717-23. https://doi.org/10.1158/1055-9965.EPI-07-0634
  23. Jones SN, Roe AE, Donehower LA, Bradley A (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature, 378, 206-8. https://doi.org/10.1038/378206a0
  24. Jung JK, Arora P, Pagano JS, Jang KL (2007). Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4acyclin D1-CDK 4/6-pRb-E2F1 pathway. Cancer Res, 67, 5771-8. https://doi.org/10.1158/0008-5472.CAN-07-0529
  25. Kowalik TF, DeGregori J, Leone G, Jakoi L, Nevins JR (1998). E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ, 9, 113-8.
  26. Leach FS, Tokino T, Meltzer P et al (1993). p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res, 53, 2231-34.
  27. Li LB, Louie MC, Chen HW, Zou JX (2008). Proto-oncogene ACTR/AIB1 promotes cancer cell invasion by up-regulating specific matrix metalloproteinase expression. Cancer Lett, 261, 64-73. https://doi.org/10.1016/j.canlet.2007.11.013
  28. Liu K, Luo Y, Tian H et al (2014). The tumor suppressor LKB1 antagonizes WNT signaling pathway through modulating GSK3beta activity in cell growth of esophageal carcinoma. Tumor Biol, 35, 995-1002. https://doi.org/10.1007/s13277-013-1133-0
  29. Louie MC, Zou JX, Rabinovich A, Chen HW (2004). ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance. Mol Cell Biol, 24, 5157-71. https://doi.org/10.1128/MCB.24.12.5157-5171.2004
  30. Lukas J, Pagano M, Staskova Z, Draetta G, Bartek J (1994). Cyclin D1 protein oscillates and is essential for cell cycle progression in human tumour cell lines. Oncogene, 9, 707-18.
  31. Luo H, Li Z, Qing Y et al (2014). Single nucleotide Polymorphisms of DNA base-excision repair genes (APE1, OGG1 and XRCC1) associated with breast cancer risk in a Chinese population. Asian Pac J Cancer Prev, 15, 1133-40. https://doi.org/10.7314/APJCP.2014.15.3.1133
  32. Martin K, Trouche D, Hagemeier C et al (1995). Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature, 375, 691-4. https://doi.org/10.1038/375691a0
  33. Mendrysa SM, McElwee MK, Michalowski J et al (2003). mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol, 23, 462-72. https://doi.org/10.1128/MCB.23.2.462-473.2003
  34. Michael D, Oren M (2003). The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol, 13, 49-58. https://doi.org/10.1016/S1044-579X(02)00099-8
  35. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B (1992). Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature, 358, 80-3. https://doi.org/10.1038/358080a0
  36. Olsson H, Hultman P, Rosell J, Soderkvist P, Jahnson S (2013). MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1. BMC Urol, 13, 5. https://doi.org/10.1186/1471-2490-13-5
  37. Onat OE, Tez M, Ozcelik T, Toruner GA (2006). MDM2 T309G polymorphism is associated with bladder cancer. Anticancer Res, 26, 3473-5.
  38. Petrocca F, Visone R, Onelli MR, et al (2008). E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell, 13, 272-86. https://doi.org/10.1016/j.ccr.2008.02.013
  39. Schiebe M, Ohneseit P, Hoffmann W et al (2000). Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors. J Neurooncol, 49, 197-203. https://doi.org/10.1023/A:1006410702284
  40. Shangary S, Wang S (2009). Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol, 49, 223-41. https://doi.org/10.1146/annurev.pharmtox.48.113006.094723
  41. Shinohara A, Sakano S, Hinoda Y et al (2009). Association of TP53 and MDM2 polymorphisms with survival in bladder cancer patients treated with chemoradiotherapy. Cancer Sci, 100, 2376-82. https://doi.org/10.1111/j.1349-7006.2009.01331.x
  42. Song H, Li Z, Deng X, et al (2014). Expression of bcl-2 and p53 in induction of esophageal cancer cell apoptosis by ECRG2 in combination with cisplatin. Asian Pac J Cancer Prev, 15, 1397-401. https://doi.org/10.7314/APJCP.2014.15.3.1397
  43. Stacey DW (2003). Cyclin D1 serves as a cell cycle regulatory switch in actively proliferating cells. Curr Opin Cell Biol, 15, 158-63. https://doi.org/10.1016/S0955-0674(03)00008-5
  44. Stender JD, Frasor J, Komm B et al (2007). Estrogen-regulated gene networks in human breast cancer cells: involvement of E2F1 in the regulation of cell proliferation. Mol Endocrinol, 21, 2112-23. https://doi.org/10.1210/me.2006-0474
  45. Su L, Li X, Gao X, et al (2014). Cytogenetic and genetic mutation features of de novo acute myeloid leukemia in elderly Chinese patients. Asian Pac J Cancer Prev, 15, 895-8. https://doi.org/10.7314/APJCP.2014.15.2.895
  46. Tuna B, Yorukoglu K, Tuzel E et al (2003). Expression of p53 and mdm2 and their significance in recurrence of superficial bladder cancer. Pathol Res Pract, 199, 323-8. https://doi.org/10.1078/0344-0338-00424
  47. Vassilev LT (2007). MDM2 inhibitors for cancer therapy. Trends Mol Med, 13, 23-31. https://doi.org/10.1016/j.molmed.2006.11.002
  48. Willander K, Ungerback J, Karlsson K et al (2010). MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia. Eur J Haematol, 85, 251-6. https://doi.org/10.1111/j.1600-0609.2010.01470.x
  49. Xiong J, Yang Q, Li J, Zhou S (2014). Effects of MDM2 inhibitors on vascular endothelial growth factor-mediated tumor angiogenesis in human breast cancer. Angiogenesis, 17, 35-50.
  50. Zawlik I, Kita D, Vaccarella S et al (2009). Common polymorphisms in the MDM2 and TP53 genes and the relationship between TP53 mutations and patient outcomes in glioblastomas. Brain Pathol, 19, 188-94. https://doi.org/10.1111/j.1750-3639.2008.00170.x
  51. Zeichner S, Alghamdi S, Elhammady G, Poppiti, R (2014). Prognostic Significance of TP53 Mutations and Single Nucleotide Polymorphisms in Acute Myeloid Leukemia:A case Series and Literature Review. Asian Pac J Cancer Prev, 15, 1603-9. https://doi.org/10.7314/APJCP.2014.15.4.1603
  52. Zhang Z, Li M, Wang H, Agrawal S, Zhang R (2003). Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc Natl Acad Sci USA, 100, 11636-41. https://doi.org/10.1073/pnas.1934692100
  53. Zhang Z, Wang H, Li M et al (2005). Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway. Oncogene, 24, 7238-47. https://doi.org/10.1038/sj.onc.1208814
  54. Zhao E, Cui D, Yuan L, Lu W (2012). MDM2 SNP309 polymorphism and breast cancer risk: a meta-analysis. Mol Biol Rep, 39, 3471-7. https://doi.org/10.1007/s11033-011-1119-1
  55. Zhou G, Zhai Y, Cui Y et al. (2007). MDM2 promoter SNP309 is associated with risk of occurrence and advanced lymph node metastasis of nasopharyngeal carcinoma in Chinese population. Clin Cancer Res, 13, 2627-33. https://doi.org/10.1158/1078-0432.CCR-06-2281

Cited by

  1. Identification of High Affinity Non-Peptidic Small Molecule Inhibitors of MDM2-p53 Interactions through Structure-Based Virtual Screening Strategies vol.16, pp.9, 2015, https://doi.org/10.7314/APJCP.2015.16.9.3759
  2. TRIP12 as a mediator of human papillomavirus/p16-related radiation enhancement effects vol.36, pp.6, 2017, https://doi.org/10.1038/onc.2016.250
  3. Exogenous C8-Ceramide Induces Apoptosis by Overproduction of ROS and the Switch of Superoxide Dismutases SOD1 to SOD2 in Human Lung Cancer Cells vol.19, pp.10, 2018, https://doi.org/10.3390/ijms19103010