High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas

Valentin-Vega, Yasmine A.; Barboza, Juan; Chau, Gilda; El‐Naggar, Adel K.; Lozano, Guillermina

doi:10.1016/j.humpath.2007.03.005

Cited by 75 publications

(69 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stronger MDMX nuclear than cytoplasmic immunostaining has been found in various tumor histotypes [32][33][34] and, despite its lack of a nuclear signal localization domain (Supplementary Figure 3), 35 it has also been reported that MDMX-S localizes in the nucleus and the cytoplasm. 16 Using an antibody that recognizes only full-length MDMX, stronger nuclear than cytoplasmic labeling was demonstrated by means of IHC in matched FFPE samples of both the WD and the DD components (Figure 3c).…”

Section: Mdmx Protein Expressionmentioning

confidence: 97%

In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas

Bozzi

Conca

Laurini

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

The molecular marker of well-differentiated/de-differentiated liposarcomas is MDM2 gene amplification coupled with protein overexpression and wild-type TP53. MDMX is a recently identified MDM2 homolog and its presence in this tumor is unexplored. Our aim was to investigate the role of full-length MDM2 and MDMX proteins and their isoforms in surgical specimens of well-differentiated/de-differentiated liposarcomas in view of Nutlin-3A (a MDM2 inhibitor) treatment. Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens was examined by means of: (1) fluorescence in situ hybridization to determine MDM2 and MDMX gene copy numbers; (2) RT-PCR and densitometry to analyze alternative splicing forms of mdm2 and mdmx; (3) immunoblotting and immunohistochemistry to assess the corresponding translated proteins; and (4) in vitro and in silico assays to determine their affinity for Nutlin-3A. All these cases showed MDM2 gene amplification with an MDMX disomic pattern. In all cases, the full-length mdm2 transcript was associated with the mdm2-b transcript, with ratios ranging from 0.07 to 5.6, and both were translated into protein; mdmx and mdmx-s were co-transcripted, with ratios ranging from 0.1 to 5.6. MDMX-S was frequently more upregulated than MDMX at both transcriptional and protein level. Each case showed different amounts of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and the corresponding proteins. In vitro assays showed that Nutlin-3A was ineffective against MDM2-B and was unable to disrupt the MDMX/TP53 and MSMX-S/TP53 complexes. Molecular simulations confirmed these in vitro findings by showing that MDM2 has high Nutlin-3A affinity, followed by MDMX-S, MDMX, and MDM2-B. Nutlin-3A is predicted to be a good therapeutic option for well-differentiated/de-differentiated liposarcomas. However, our findings predict heterogeneous responses depending on the relative expression of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and proteins. Well-differentiated/de-differentiated (WD/DD) liposarcomas (LPS) account for 40% of all liposarcomas. With a few exceptions, 1,2 the DD component is defined as a usually abrupt and generally a phenotypic time-dependent transition to a non-lipogenic sarcoma.WD/DD LPS characteristically involve the retroperitoneum and are characterized by a high rate of local recurrences. The inability of even aggressive surgery to obtain negative margins leads to high local failure rates, worsening the long-term prognosis of WD/DD patients and favors the use of multiple treatment modalities albeit with limited benefit. 3,4 The molecular hallmark of WD/DD LPS is MDM2 gene amplification coupled with protein overexpression and wild-type TP53, 5-7 which provides the rationale supporting the therapeutic potential of the MDM2 antagonist Nutlin-3A. MDM2 is an E3 ubiquitin ligase that, in addition to targeting TP53 for proteasomal degradation, blocks TP53

show abstract

Section: Mdmx Protein Expressionmentioning

confidence: 97%

In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas

Bozzi

Conca

Laurini

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…115 Many tumors including sarcomas and head and neck squamous carcinomas indeed have high levels of Mdm2 and retain a wild-type p53 gene. 116,117 However, this is not always the case as some tumors have high levels of Mdm2 and mutations in p53. 118,119 These tumor data suggest that cells expressing high levels of Mdm2 have additional growth advantages that fuel tumorigenesis.…”

Section: P53-independent Functions Of Mdm2mentioning

confidence: 99%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

View full text Add to dashboard Cite

The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

show abstract

“…Amplified expression of either MDM2 and MDMX, in which both are known as p53 inhibitors would severely degrade the protein, resulting in apoptotic blockade. Indeed, MDM2 is overexpressed in a variety of human cancers in HNSCC and has become a prognostic marker (Valentin-Vega et al, 2007;Huang et al, 2001;Ganly et al, 2000;Matsumura et al, 1996). The G-allele single nucleotide polymorphism at 309 of MDM2 (MDM2 SNP309G) has been shown to be associated with significantly higher levels of the www.intechopen.com …”

Section: Dysfunctions Of P53-mediated Apoptotic Pathway In Hnsccmentioning

confidence: 99%

“…MDM2 overexpression also induces centrosome hyperamplification and chromosome in cultured HNSCC cells (Caroll et al, 1999). The scenario may become worse when MDMX are excessively co-expressed as reported in a study in which majority of tumors with amplified MDM2 were also positive for MDMX (Valentin-Vega et al, 2007). Since MDMX potentiates MDM2, overexpression of MDMX may accelerate the p53 degradation and subsequently result in abrogation of p53-mediated apoptotic pathway.…”

mentioning

confidence: 97%