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

Giglio, Simona; Mancini, Francesca; Gentiletti, Francesca; Sparaco, Giorgia; Felicioni, Lara; Barassi, Fabio; Martella, Carla; Prodosmo, Andrea; Iacovelli, Stefano; Buttitta, Fiamma; Farsetti, Antonella; Soddu, Silvia; Marchetti, Antonio; Sacchi, Ada; Pontecorvi, Alfredo; Moretti, Fabiola

doi:10.1158/0008-5472.can-05-0450

Cited by 58Cancer-related Molecular PathwaysHeat shock proteins researchUbiquitin and proteasome pathways

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

Giglio, Simona, Mancini, Francesca, Gentiletti, Francesca, Sparaco, Giorgia, Felicioni, Lara, Barassi, Fabio, Martella, Carla, Prodosmo, Andrea +8 more·2005·Cancer Research

DOI 10.1158/0008-5472.can-05-0450

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Abstract

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.

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Human tumors with MDMX overexpression may also have inactivated p53, indicating a potential oncogenic benefit from Mdmx overexpression in addition to p53 inhibition.
“Moreover, human tumors with MDMX overexpression may also have inactivated p53,3,19,30,31 which indicates a potential oncogenic benefit to the cancer cells from Mdmx overexpression in addition to its inhibition of p53.”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [30]
Mdmx has p53-independent functions.
“the identification of Mdmx overexpression in tumors with mutated or deleted p53 and effects of Mdmx on genome instability in cells lacking p53 indicate p53-independent functions of Mdmx.3,19,30–33”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [30]
Some tumor cells contain both inactivated TP53 and overexpressed MDM2 and/or MDM4.
“some tumor cells contain both inactivated TP53 and overexpressed MDM2 and/or MDM4”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Giglio, et al., 2005

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Authors: Giglio, S., Mancini, F., Gentiletti, F., Sparaco, G., Felicioni, L., Barassi, F., Martella, C., Prodosmo, A., Iacovelli, S., Buttitta, F., Farsetti, A., Soddu, S., Marchetti, A., Sacchi, A., Pontecorvi, A., & Moretti, F.
Affiliations: Instituto Nazionale Tumori Regina Elena (IT)
Università Cattolica del Sacro Cuore (IT)
University of Chieti-Pescara (IT)
Institute of Neurobiology and Molecular Medicine (IT)
ORCID: Giglio, Simona
Prodosmo, Andrea
Iacovelli, Stefano
Farsetti, Antonella
Soddu, Silvia
Pontecorvi, Alfredo
Moretti, Fabiola
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2005-11-01
Volume: 65
Issue: 21
Pages: 9687-9694
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-05-0450
OpenAlex: W2117450502
Cited by: 58
References: 45
Citations by year: 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 4
FWCI: 2.02
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: HDMX, aberrant splicing, MDM2, p53 stabilization, p53 degradation, p53-binding domain, RING domain, lung cancer, chemosensitivity, tumor phenotype
MeSH terms: Animals, Humans, Nuclear Proteins, Proto-Oncogene Proteins, RNA, Messenger, Thyroid Neoplasms, Transfection, Tumor Suppressor Protein p53, Alternative Splicing, Cell Cycle Proteins, Protein Isoforms, NIH 3T3 Cells, Cell Line, Tumor, Cell Growth Processes, Mice, Proto-Oncogene Proteins c-mdm2

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

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