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An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2

Oncogene volume 20, pages 4041–4049 (2001)Cite this article

Abstract

The human counterpart hdm2 of the murine double-minute 2 (mdm2) gene encodes a 90-kD protein (HDM2) that inhibits the function of the p53 tumor suppressor. Hdm2 is amplified in approximately 30% of sarcomas, leading to overproduction of HDM2 and inactivation of p53. Using immunohistochemistry to screen a panel of human tumors for HDM2 overproduction, we detected high levels of HDM2 in the cytoplasm in 25% of lung tumors as opposed to its normal localization in the nucleus. These samples contained full-length hdm2 and several alternate-splice forms of hdm2 mRNA. Sequence analysis revealed deletions in the alternate-splice forms of the p53 binding domain and absence of a nuclear localization signal. In transient transfection assays, one of the alternate-splice forms, HDM2ALT1, bound and sequestered full-length HDM2 in the cytoplasm. In addition, the binding of HDM2ALT1 to HDM2 inhibited the interaction of HDM2 with p53, thus enhancing p53 transcriptional activity. These data suggest the existence of another level of regulation of HDM2 which increases the activity of p53.

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Acknowledgements

We thank Carolyn Foster and Dwight Oliver for their technical assistance. This research was supported by grants from the NIH (CA47296 and CA34936) and a SPORE development award (CA70907). Susan Evans was a recipient of the Theodore Law UCF Scientific Achievement Fellowship and a Pharmacia SR002011 grant.

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Authors and Affiliations

  1. Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Susan C Evans, Meena Viswanathan, Jason D Grier, Meera Narayana & Guillermina Lozano

  2. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Adel K El-Naggar

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  1. Susan C Evans
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  2. Meena Viswanathan
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Correspondence to Guillermina Lozano.

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Evans, S., Viswanathan, M., Grier, J. et al. An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 20, 4041–4049 (2001). https://doi.org/10.1038/sj.onc.1204533

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