The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants

  • Authors:
    • Doris R. Brown
    • Debabrita Deb
    • Rebecca Frum
    • Laura Hickes
    • Ruben Munoz
    • Sumitra Deb
    • Swati Palit Deb
  • View Affiliations

  • Published online on: March 1, 2001     https://doi.org/10.3892/ijo.18.3.449
  • Pages: 449-459
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Abstract

Human MDM2 (hMDM2) inhibits transcriptional activation mediated by wild-type p53 and its tumor-derived mutants. We present evidence to show that hMDM2 interacts with the tumor-derived mutants of p53 and inhibits transcriptional activation of the human c-myc promoter mediated by the tumor-derived mutants of p53 through two domains. These two domains of hMDM2 are able to function independent of each other. Interaction with either of the domains is sufficient for inhibition of mutant p53-mediated transactivation. One of these domains is the same as the wild-type p53 interaction domain of hMDM2, whereas a second domain is situated within amino acid 190 and 276 residues and is specific for mutant p53. hMDM2 does not inhibit transcriptional activation mediated by the transcriptional activator VP16, suggesting that the inhibition is not mediated by inactivation of a general transcription factor. The transactivation and the oligomerization domains of mutant p53 are dispensable for its interaction with hMDM2. Thus, both hMDM2 and p53 recognize each other through unique domains. These observations suggest that forms of hMDM2 incapable of interacting with the wild-type p53, and are often expressed in transformed cells, would inhibit mutant p53-mediated transactivation and antagonize the tumorigenic function of mutant p53. This inhibitory function of hMDM2 may account for infrequent co-occurrence of p53 mutation and hMDM2 overexpression in cancer cells. Our results also suggest distinct mechanisms for wild-type and mutant p53-mediated transcriptional activation.

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March 2001
Volume 18 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Brown DR, Deb D, Frum R, Hickes L, Munoz R, Deb S and Deb SP: The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants. Int J Oncol 18: 449-459, 2001.
APA
Brown, D.R., Deb, D., Frum, R., Hickes, L., Munoz, R., Deb, S., & Deb, S.P. (2001). The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants. International Journal of Oncology, 18, 449-459. https://doi.org/10.3892/ijo.18.3.449
MLA
Brown, D. R., Deb, D., Frum, R., Hickes, L., Munoz, R., Deb, S., Deb, S. P."The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants". International Journal of Oncology 18.3 (2001): 449-459.
Chicago
Brown, D. R., Deb, D., Frum, R., Hickes, L., Munoz, R., Deb, S., Deb, S. P."The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants". International Journal of Oncology 18, no. 3 (2001): 449-459. https://doi.org/10.3892/ijo.18.3.449