Abstract
Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249) is critical during the formation of hepatocellular carcinoma (HCC) following hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin-like growth factor II (IGF-II) transcription largely from promoter 4, accumulating the fetal form of IGF-II. Modulation of the transcription factor binding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promoter, while p53mt249 enhanced the formation of transcriptional complexes through enhanced DNA-protein (Sp1 or TBP) and protein–protein (Sp1 and TBP) interactions. p53mt249 stimulates transcription factor Sp1 phosphorylation which might be a cause of increased transcription factor binding on the P4 promoter while wild-type p53 does not. Transfection of hepatocytes with p53mt249 impaired induction of apoptosis by the HBV-X protein and TNF-α. Therefore, the blocking of apoptosis through enhanced production of IGF-II should provide a favorable opportunity for the selection of transformed hepatocytes. These results explain the molecular basis for the genesis of HCC by p53mt249 which was found to be induced by a potent mutagen, AFB1.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aguilar F, Hussain SP and Cerutti P. . 1993 Proc. Natl. Acad. Sci. USA 90: 8586–8590.
Bressac B, Kew M, Wands J and Ozturk M. . 1991 Nature 350: 429–431.
Cariani E, Lasserre C, Seurin D, Hamenn B, Franco D and Czech MP. . 1988 Cancer Res. 48: 6844–6849.
Daughaday JR and Rotwein P. . 1989 Endocrinol. Rev. 10: 68–91.
Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M, Finlay C and Levine AJ. . 1993 Nature Genet. 4: 42–46.
Friend S. . 1994 Science 265: 334–355.
Fu XX, Lee YI, Su CU, Hintz R, Biempica L, Schneider R and Rogler CE. . 1998 J. Virol. 62: 4322–4330.
Funk WD, Pak DT, Karas RH, Wright WE and Shay JW. . 1992 Mol. Cell. Biol. 12: 2866–2871.
Gorman CM, Moffat LF and Howard BH. . 1982 Mol. Cell. Biol. 2: 1044–1051.
Greenblatt MS, Bennett WP, Hollstein M and Harris CC. . 1994 Cancer Res. 55: 4855–4878.
Gualberto A, Aldape K, Kozakiewicz K and Tlsty T. . 1998 Proc. Natl. Acad. Sci. USA 95: 5166–5171.
Holthuizen P, Lee FM, Ikejiri K, Yamamoto M and Sussenbach JS. . 1990 Biophys. Acta. 1087: 341–343.
Hsiao M, Low J, Dorn E, Ku D, Pattengale P, Yeargin J and Haas M. . 1994 Am. J. Pathol. 145: 702–714.
Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ and Harris CC. . 1991 Nature (Lond) 350: 427–428.
Hulla JE, Chen ZY and Eatan DL. . 1993 Cancer Res. 53: 9–11.
Hyun SW, Kim SJ, Park KC, Rho HM and Lee YI. . 1993 FEBS Lett. 332: 153–158.
Kim SJ, Onwuta US, Lee YI, Li R, Botchan MR and Robbins PD. . 1992 Mol. Cell. Biol. 12: 2455–2463.
Kim SO, Park JG and Lee YI. . 1996 Cancer Res. 56: 3831–3836.
Kim YS and Kang HS. . 1984 Korean Biochem. J. 17: 7076–7081.
Lamas E, Bail LB, Boucher O, Heusset C and Brechet C. . 1989 Falk Symposium; Oct. 15–17 Basel, Switzerland. 55: 45–58.
Lee YI, Lee S, Lee YI, Bong YS, Hyun SW, Yoo YD, Kim SJ, Kim YW and Poo HR. . 1998 Oncogene 16: 2367–2380.
Luis P, Gonzale-Garcia H, Page M and Nunez G. . 1997 Science 278: 687–689.
Luse DS and Roeder RG. . 1980 Cell 20: 691–699.
O'Reilly DR, Miller LK and Luckow VA. . 1992 Baculovirus Expression Vectors: A Laboratory Manual. V1 W. H. Freeman Company, New York, NY.
Ozturk MA. . 1991 Lancet 338: 1356–1359.
Perrem K, Rayner J, Voss T, Sturzbecker H, Jackson P and Braithvaite A. . 1995 Oncogene 11: 1299–1307.
Sandeep RD, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME. . 1997 Cell 91: 231–247.
Shivakumar C and Das GC. . 1996 Oncogene 13: 323–332.
Su F and Schneider RJ. . 1997 Proc. Natl. Acad. Sci. USA 94: 8744–8749.
Su JJ, Qin GZ, Yan R, Huang D, Yang C, Huang G and Lotlikar PD. . 1997 Exp. Mol. Med. 29: 177–182.
Ueda K and Ganem D. . 1996 J. Virol. 70: 1375–1383.
Yan RQ, Su JJ, Huang DR, Gan YC, Yang C and Huang GH. . 1996 Cancer Res. Clin. Oncol. 122: 289–295.
Yang D, Faris R, Hixson D, Affigne S and Rogler C. . 1996 J. Virol. 70: 6260–6268.
Yeh ES, Yu MC, Mo CC, Luo S, Tong MJ and Henderson BE. . 1989 Cancer Res. 49: 2506–2509.
Zhang L, Zhan Q, Zhan S, Kashanchi F, Fornace A, Seth P and Helman L. . 1998 DNA Cell Biol. 17: 125–131.
Acknowledgements
We thank Dr R Tjian at the Howard Hughes Medical Institute at the University of California for generously supplying pSp1(pPacSp1) expression plasmid and control vector pSp1-0 (pPac0). This work was supported by grants from the Korea Ministry of Science and Technology (KS1120, KG1182).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lee, Y., Lee, S., Das, G. et al. Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. Oncogene 19, 3717–3726 (2000). https://doi.org/10.1038/sj.onc.1203694
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203694
Keywords
This article is cited by
-
The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets
Infectious Agents and Cancer (2014)
-
Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme
Tumor Biology (2013)
-
Targeting insulin-like growth factor axis in hepatocellular carcinoma
Journal of Hematology & Oncology (2011)
-
When mutants gain new powers: news from the mutant p53 field
Nature Reviews Cancer (2009)
-
Transcription regulation by mutant p53
Oncogene (2007)