A functional p53-responsive intronic promoter is contained within the human mdm2 gene
Open accessAbstract
The mdm2 gene is a target for transcriptional activation by the p53 tumor suppressor gene product. Previous work has revealed that the mouse mdm2 gene contains two promoters: one is located upstream to the gene and is active in the absence of p53, the other resides within the first intron and requires p53 for transcriptional activity. To determine whether this unique promoter activation pattern is biologically important, we investigated the structure and function of the corresponding region of the human mdm2 (hmdm2) gene. We report here that the hmdm2 gene also contains an intronic, p53-dependent promoter. The structural features of this promoter are highly conserved between mouse and man, as opposed to the lack of conservation of the first exon. This promoter is triggered in vivo in the presence of activated wild type p53, leading to the production of novel mRNA species. The intronic hmdm2 promoter contains two tandem p53 binding elements. Deletion analysis suggests that optimal promoter activity requires the simultaneous binding of p53 to both elements; this may serve to prevent premature triggering of the promoter by p53.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In MDM2, p53 binding to the first intron leads to the formation of transcripts that differ from the constitutionally expressed MDM2 isoform.
“In case of MDM2, for example, p53 binding to the first intron leads to the formation of transcripts that differ from the constitutionally expressed MDM2 isoform.67, 68”
From Census and evaluation of p53 target genes (2017) · cites this paper as [68]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113 · see citing works
Kastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90593-2 · Cited by 3,047 · see citing works
Definition of a consensus binding site for p53
El-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W., & Vogelstein, B. (1992) · Nature Genetics · doi:10.1038/ng0492-45 · Cited by 1,985 · see citing works
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949 · see citing works
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801 · see citing works
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,447 · see citing works
mdm2 expression is induced by wild type p53 activity.
Barak, Y., Juven, T., Haffner, R., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05678.x · Cited by 1,290 · see citing works
Self-citationMichalovitz, D., Halevy, O., & Oren, M. (1990) · Cell · doi:10.1016/0092-8674(90)90113-s · Cited by 769 · see citing works
Self-citationA Transcriptionally Active DNA-Binding Site for Human p53 Protein Complexes
Funk, W. D., Pak, D. T. S., Karas, R. H., Wright, W. E., & Shay, J. W. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.6.2866 · Cited by 732 · see citing works
Fakharzadeh, S. S., Trusko, S. P., & George, D. L. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb07676.x · Cited by 704 · see citing works
Wild-type p53 can inhibit oncogene-mediated focus formation.
Eliyahu, D., Michalovitz, D., Eliyahu, S., Pinhasi-Kimhi, O., & Oren, M. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.8763 · Cited by 681 · see citing works
Self-citationReifenberger, G., Liu, L., Ichimura, K., Schmidt, E., & Collins, V. P. (1993) · PubMed · Cited by 562 · see citing works
p53 Mutation and MDM2 amplification in human soft tissue sarcomas.
Leach, F. S., Tokino, T., Meltzer, P. S., Burrell, M., Oliner, J., Smith, S., HILL, D. E., Sidransky, D., Kinzler, K. W., & Vogelstein, B. (1993) · PubMed · Cited by 533 · see citing works
(1994) · PubMed · Cited by 509 · see citing works
Cyclin G is a transcriptional target of the p53 tumor suppressor protein.
Okamoto, K., & Beach, D. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06807.x · Cited by 455 · see citing works
MDM2 gene amplification in metastatic osteosarcoma.
Ladanyi, M., Cha, C. H., Lewis, R., Jhanwar, S. C., Huvos, A. G., & Healey, J. H. (1993) · PubMed · Cited by 342 · see citing works
Donehower, L. A., & Bradley, A. (1993) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(93)90004-v · Cited by 333 · see citing works
Juven‐Gershon, T., Barak, Y., Zauberman, A., George, D. L., & Oren, M. (1993) · PubMed · Cited by 332 · see citing works
Self-citationBarak, Y., Gottlieb, E., Juven-Gershon, T., & Oren, M. (1994) · Genes & Development · doi:10.1101/gad.8.15.1739 · Cited by 328 · see citing works
Self-citationThe mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth.
Finlay, C. A. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.301 · Cited by 311 · see citing works
Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway.
Chen, C. Y., Oliner, J., Zhan, Q., Fornace, A. J., Vogelstein, B., & Kastan, M. B. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.7.2684 · Cited by 271 · see citing works
The mdm-2 gene is induced in response to UV light in a p53-dependent manner.
Perry, M. E., Piette, J., Zawadzki, J., Harvey, D., & Levine, A. J. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.24.11623 · Cited by 247 · see citing works
A Transcriptionally Active DNA-Binding Site for Human p53 Protein Complexes
Funk, W. D., Pak, D. T. S., Karas, R. H., et al. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.6.2866-2871.1992 · Cited by 239 · see citing works
Binding of a simian virus 40 T antigen-related protein to DNA
McKay, R. D. G. (1981) · Journal of Molecular Biology · doi:10.1016/0022-2836(81)90540-4 · Cited by 232 · see citing works
Regulation of Transcription Functions of the p53 Tumor Suppressor by the mdm-2 Oncogene
Chen, J., Lin, J., & Levine, A. J. (1995) · Molecular Medicine · doi:10.1007/bf03401562 · Cited by 214 · see citing works
Picksley, S. M., & Lane, D. P. (1993) · BioEssays · doi:10.1002/bies.950151008 · Cited by 207 · see citing works
Halazonetis, T. D., & Kandil, A. N. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06199.x · Cited by 205 · see citing works
Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes.
Olson, D. C., Maréchal, V., Momand, J. A., Chen, J., Romocki, C., & Levine, A. J. (1993) · PubMed · Cited by 188 · see citing works
Biochemical properties and biological effects of p53
Haffner, R., & Oren, M. (1995) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(95)90058-6 · Cited by 177 · see citing works
Self-citationp53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest.Preprint
Ewen, M. E., Oliver, C. J., Sluss, H. K., Miller, S. J., & Peeper, D. S. (1995) · Genes & Development · doi:10.1101/gad.9.2.204 · Cited by 165 · see citing works
Zauberman, A., Barak, Y., Ragimov, N., Levy, N., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05941.x · Cited by 151 · see citing works
Self-citationp53-mediated apoptosis in HeLa cells can be overcome by excess pRB.
Haupt, Y., Rowan, S., & Oren, M. (1995) · PubMed · Cited by 133 · see citing works
Self-citationp53 oligomerization and DNA looping are linked with transcriptional activation.
Stenger, J. E., Tegtmeyer, P., Mayr, G. A., Reed, M. J., Wang, Y., Wang, P., Hough, P. V. C., & Mastrangelo, I. A. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06947.x · Cited by 131 · see citing works
The p53 tumor suppressor protein: meeting review.Preprint
Prives, C. L., & Manfredi, J. J. (1993) · Genes & Development · doi:10.1101/gad.7.4.529 · Cited by 120 · see citing works
Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53‐mediated growth arrest.
Barak, Y., & Oren, M. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05270.x · Cited by 119 · see citing works
Self-citationThe mdm-2 Oncogene Can Overcome Wild-Type p53 Suppression of Transformed Cell Growth
Finlay, C. A. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.301-306.1993 · Cited by 83 · see citing works
Upregulation of mdm-2 expression in Meth A tumor cells tolerating wild-type p53.
Otto, A., & Deppert, W. (1993) · PubMed · Cited by 41 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- Chen.C.Y, Oliner,DJ., Zhan.Q., FomaceJ.A JR., Vogelstem.B. and Kastan.B.M. (1994) Proc. Nail. Acad. Sci. USA 91, 2684-2688.
- PerryJvi.E., PietteJ., ZawadzkiJA, Harvey.D. and LevineAJ. (1993) Proc. Nail. Acad. Sci. USA 90, 11623-11627.
- ZaubermanA, LupoA and Oren,M-(1995) Oncogene, in press.
- Eliyahu.D., Michalovitz,D., Ehyahu.S., Pinhasi-Kimhi.O. and Orenjvi. (1989) Proc. Natl. Acad. Sci. USA 86, 8763-8767.
- McKay.R. (1981) /. Mol. Biol. 145, 471^*88. Downloaded from https://academic.oup.com/nar/article/23/14/2584/1016866 by guest on 24 December 2023
Cited by
Sorted by citations
Transcriptional control of human p53-regulated genes
Riley, T., Sontag, E., Chen, P., & Levine, A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2395 · Cited by 1,921 · see citing works
Bond, G. L., Hu, W., Bond, E. E., Robins, H., Lutzker, S. G., Arva, N. C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.022 · Cited by 1,265 · see citing works
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs
Müller, M., Wilder, S., Bannasch, D., Israeli, D., Lehlbach, K., Li-Weber, M., Friedman, S. L., Galle, P. R., Stremmel, W., Oren, M., et al. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.11.2033 · Cited by 878 · see citing works
Self-citationMDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Roth, J., Dobbelstein, M., Freedman, D. A., Shenk, T., & Levine, A. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.2.554 · Cited by 610 · see citing works
Takimoto, R., & El-Deiry, W. S. (2000) · Oncogene · doi:10.1038/sj.onc.1203489 · Cited by 360 · see citing works
Opposing Effects of Ras on p53
Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F. (2000) · Cell · doi:10.1016/s0092-8674(00)00123-9 · Cited by 357 · see citing works
Self-citationThe Mdm2–p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor
Manfredi, J. J. (2010) · Genes & Development · doi:10.1101/gad.1941710 · Cited by 344 · see citing works
Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38189 · Cited by 286 · see citing works
MDM2 Promotes Cell Motility and Invasiveness by Regulating E-Cadherin Degradation
Yang, J.-Y., Zong, C. S., Xia, W., Wei, Y., Ali-Seyed, M., Li, Z., Broglio, K., Berry, D. A., & Hung, M.-C. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00172-06 · Cited by 211 · see citing works
The transcription factor p53: Not a repressor, solely an activator.
Fischer, M., Steiner, L., & Engeland, K. (2014) · Cell Cycle · doi:10.4161/15384101.2014.949083 · Cited by 153 · see citing works
Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
de Graaf, P., Little, N. A., Ramos, Y. F. M., Meulmeester, E., Letteboer, S. J. F., & Jochemsen, A. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213034200 · Cited by 143 · see citing works
Masuya, D., Huang, C., Liu, D., Nakashima, T., Yokomise, H., Ueno, M., Nakashima, N., & Sumitomo, S. (2006) · The Journal of Pathology · doi:10.1002/path.1931 · Cited by 103 · see citing works
Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53
Jordan, J. J., Menendez, D., Inga, A., Nourredine, M., Bell, D., & Resnick, M. A. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000104 · Cited by 103 · see citing works
Staf50 is a novel p53 target gene conferring reduced clonogenic growth of leukemic U-937 cells
Obad, S., Brunnström, H., Vallon-Christersson, J., Borg, Å., Drott, K., & Gullberg, U. (2004) · Oncogene · doi:10.1038/sj.onc.1207524 · Cited by 90 · see citing works
Phillips, A., Teunisse, A., Lam, S., Lodder, K., Darley, M., Emaduddin, M., Wolf, A., Richter, J., de Lange, J., Verlaan-de Vries, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.129726 · Cited by 55 · see citing works
- Authors
- Zauberman, A., Flusberg, D., Haupt, Y., Barak, Y., & Oren, M.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Oren, Moshe
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 1995
- Volume
- 23
- Issue
- 14
- Pages
- 2584-2592
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC307078
- OpenAlex
- W2058737236
- Cited by
- 276
- References
- 38
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 9 · 2016: 4 · 2015: 12 · 2014: 12 · 2013: 9 · 2012: 11
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Minerva Foundation
- National Cancer Institute (R01CA040099)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2 gene, p53, intronic promoter, transcriptional activation, p53 tumor suppressor
- MeSH terms
- Animals, Base Sequence, DNA, Humans, Introns, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Sequence Homology, Nucleic Acid, Species Specificity, Tumor Cells, Cultured, Genes, p53, Conserved Sequence, DNA Primers, Mice, Proto-Oncogene Proteins c-mdm2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
