This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Giglio, S. Articles by Moretti, F. Search for Related Content PubMed PubMed Citation Articles by Giglio, S. Articles by Moretti, F.

Identification of an Aberrantly Spliced Form of HDMX in Human Tumors: A New Mechanism for HDM2 Stabilization

¹ Laboratory of Molecular Oncogenesis, Regina Elena Cancer Institute; ² Institute of Neurobiology and Molecular Medicine, National Council of Research; ³ Institute of Medical Pathology, Catholic University, Rome, Italy; and ⁴ Clinical Research Center, Center of Excellence on Aging, University Foundation, Chieti, Italy

Requests for reprints: Fabiola Moretti, Laboratory of Molecular Oncogenesis, Regina Elena Cancer Institute, Via delle Messi D'Oro 156, 00158 Rome, Italy. Phone: 39-06-52662531; Fax: 39-06-4180526; E-mail: moretti{at}ifo.it.

The HDMX protein is closely related to HDM2 with which it shares different structural domains, particularly the p53 binding domain and the ring finger domain, where the two HDM proteins interact. Several oncogenic forms derived from splicing of HDM2 have been described in cancer. This work aimed at investigating whether analogous forms of HDMX exist in human tumors. Here, we report the characterization of an aberrantly spliced form of HDMX, HDMX211, isolated from the thyroid tumor cell line, ARO. HDMX211 binds and stabilizes the HDM2 protein. Although it lacks the p53 binding domain, HDMX211 also stabilizes p53 by counteracting its degradation by HDM2. However, the resulting p53 is transcriptionally inactive and increasingly associated to its inhibitor HDM2. Expression of HDMX211 strongly enhances the colony-forming ability of human cells in the presence or absence of wild-type p53. Conversely, depletion of HDMX211 by small interfering RNA significantly reduces the growth of ARO cells and increases their sensitivity to chemotherapy. Screening of lung cancer biopsies shows the presence of HDMX211 in samples that overexpress HDM2 protein, supporting a pathologic role for this new protein. This is the first evidence of a variant form of HDMX that has oncogenic potential independently of p53. HDMX211 reveals a new mechanism for overexpression of the oncoprotein HDM2. Most interestingly, it outlines a possible molecular explanation for a yet unclarified tumor phenotype, characterized by simultaneous overexpression of HDM2 and wild-type p53.

This article has been cited by other articles:

				M. Wade and G. M. Wahl Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry? Mol. Cancer Res., January 1, 2009; 7(1): 1 - 11. [Abstract] [Full Text] [PDF]

				A. Forslund, Z. Zeng, L.-X. Qin, S. Rosenberg, M. Ndubuisi, H. Pincas, W. Gerald, D. A. Notterman, F. Barany, and P. B. Paty MDM2 Gene Amplification Is Correlated to Tumor Progression but not to the Presence of SNP309 or TP53 Mutational Status in Primary Colorectal Cancers Mol. Cancer Res., February 1, 2008; 6(2): 205 - 211. [Abstract] [Full Text] [PDF]

				J.-C. W. Marine, M. A. Dyer, and A. G. Jochemsen MDMX: from bench to bedside J. Cell Sci., February 1, 2007; 120(3): 371 - 378. [Abstract] [Full Text] [PDF]

				B. R. Binder A Novel Application for Murine Double Minute 2 Antagonists: The p53 Tumor Suppressor Network Also Controls Angiogenesis Circ. Res., January 5, 2007; 100(1): 13 - 14. [Full Text] [PDF]

				D. S. Chandler, R. K. Singh, L. C. Caldwell, J. L. Bitler, and G. Lozano Genotoxic Stress Induces Coordinately Regulated Alternative Splicing of the p53 Modulators MDM2 and MDM4 Cancer Res., October 1, 2006; 66(19): 9502 - 9508. [Abstract] [Full Text] [PDF]

				A. Srebrow and A. R. Kornblihtt The connection between splicing and cancer J. Cell Sci., July 1, 2006; 119(13): 2635 - 2641. [Abstract] [Full Text] [PDF]

				J. T. Patton, L. D. Mayo, A. D. Singhi, A. V. Gudkov, G. R. Stark, and M. W. Jackson Levels of HdmX Expression Dictate the Sensitivity of Normal and Transformed Cells to Nutlin-3. Cancer Res., March 15, 2006; 66(6): 3169 - 3176. [Abstract] [Full Text] [PDF]

				C. C. Harris Protein-protein interactions for cancer therapy PNAS, February 7, 2006; 103(6): 1659 - 1660. [Full Text] [PDF]