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 51 publications

(54 citation statements)

References 35 publications

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“…HDMX211 binds and stabilizes HDM2 and also counteracts HDM2-mediated p53 degradation. 22 Interestingly, Western blot analysis of one of three ALL cases showed the presence of an additional band at B30 kDa, suggesting that some pre-B ALL cases have both HDM4 and HDM4-S forms. The antibody against HDM4 and primers for RT-PCR used in this study will not detect the protein or mRNA of the HDMX211 variant according to the reported sequence.…”

Section: Discussionmentioning

confidence: 94%

HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target

Han

McDonnell²,

Lozano³

et al. 2007

Modern Pathology

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Human homolog of murine double minute 2 (HDM2) and HDM4 (or HDMX) are negative regulators of p53. HDM4 has not been assessed in precursor B (pre-B) lymphoblastic leukemia (ALL). We examined bone marrow samples obtained at time of diagnosis from 55 adults with pre-B ALL. A tissue microarray composed of 2 cores per specimen was constructed and immunohistochemical techniques were used to assess HDM4, HDM2, p53, and p21. HDM4 was expressed in 39 of 49 (80%) cases. HDM2 was expressed in 14 of 54 (26%). All HDM2-positive cases were also positive for HDM4 (Po0.05). We confirmed expression of HDM4 and HDM4 variants by Western blotting and sequencing of reverse transcription-polymerase chain reaction products in a subset of ALL tumors. Results were correlated with the presence of the Philadelphia chromosome (Ph). p53 (Po0.05) and p21 (Po0.001) were expressed significantly more often in Ph þ pre-B ALL. HDM4 and HDM2 showed no correlation with Ph status. HDM4 expression in most cases of adult pre-B ALL suggests that HDM4 is a potential therapeutic target. Modern Pathology (2007) 20, 54-62.

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Section: Discussionmentioning

confidence: 94%

HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target

Han

McDonnell²,

Lozano³

et al. 2007

Modern Pathology

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“…29 HDM-A lacks exon 9 sequences encoding the acidic domain and, as a result, cannot stabilize HDM2 and is susceptible to HDM2-initiated degradation.…”

Section: Discussionmentioning

confidence: 99%

HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis

et al. 2010

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In mouse models and cell lines, murine double minute 2 (MDM2) and MDM4 have been shown to synergistically promote proteasome-mediated degradation of p21 and p53. MDM4 also inhibits p53-mediated transcriptional activation of p21. p53 expression results in increased p21 expression, a negative cell-cycle regulatory protein and an inhibitor of cyclin D1. As mantle cell lymphoma is characterized by cyclin D1 overexpression, we assessed for human homolog of MDM4 (HDM4) expression and its effect on p21 in mantle cell lymphoma. Using immunohistochemical methods, in reactive lymph nodes (n ¼ 19) germinal center cells strongly expressed HDM4 in the nucleus and the cytoplasm, but mantle zone B-cells were only dimly positive. In mantle cell lymphoma tumors, aberrant HDM4 nuclear expression was observed in 18 of 19 (95%) cases. In contrast, HDM4 in other B-cell non-Hodgkin lymphoma types retained its normal pattern of expression. To further characterize the differential upregulation of HDM4 in mantle cell lymphoma, HDM4 was assessed by quantitative real-time polymerase chain reaction in four mantle cell lymphoma cell lines (Granta 519, Z-138, SP-53, and Mino) and six mantle cell lymphoma tumors. Both the splicing variant HDM4-S, containing only the p53-binding domain, and full length HDM4 were increased compared with normal CD19 þ B-cells (Po0.05). Using small interfering RNA to inhibit HDM4 in the SP53 and Mino cell lines showed increased p21 and active caspase-3, the latter indicating increased apoptosis. Our results show that HDM4 is overexpressed in mantle cell lymphoma and, at least in part, exerts its effect by suppressing p21 expression, thereby enhancing cell-cycle progression. Inhibition of HDM4 may serve as a potential approach in the design of therapy for patients with mantle cell lymphoma.

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“…Probably the high expression level of DDX39 in the lymphoid tissues exceeds the capacity of splicing machinery to regulate the accurate splicing pattern, 27 thereby generating DDX39-SS. The biological significance of the COOH terminally truncated variants of DDX39, DDX39-S and -SS, is unclear but they could take part in tumor development in some way 28 because DDX39 may form a dimer structure using the NH 2 terminal domain, as inferred from the crystal structure of UAP56. 29 Since among the three variants, DDX39-L is the only transcript likely overexpressed in LSCC and preserves all the motifs necessary for RNA helicase activity, we examined recombinant DDX39-L produced in the baculoviral system for RNA helicase-related activities.…”

Section: Discussionmentioning

confidence: 99%

DDX39, upregulated in lung squamous cell cancer, displays RNA helicase activities and promotes cancer cell growth

Sugiura

Nagano²,

Noguchi³

2007

Cancer Biology & Therapy

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KeY wordSDDX39, DEAD box proteins, lung squamous cell carcinoma, microarray; RNA helicase AbbreviATioNS HNBEhuman normal bronchial epithelial cells LAC lung adenocarcinoma LSCC lung squamous cell carcinoma MGFP monster green fluorescent protein NSCLC non-small-cell lung cancer AcKNowledgemeNTSWe thank Drs. Shigeaki Katoh and Thomas J. Hope for their kind gifts (pCH110 and pDM138, respectively) and Dr. Kentaro Miyamoto for image visualization. We are also indebted to Aya Yamaguchi and Rie Ikeda for sequencing. [Cancer Biology & Therapy 6:6, 957-964; June 2007]; ©2007 Landes Bioscience AbSTrcTTo explore differentially expressed genes involved in non-small cell lung cancer progression, we used the gene expression profile database of various human tissues and identified DDX39, a new member of the DEAD box RNA helicases, showing overexpression in human lung squamous cell carcinoma (LSCC) but not in lung adenocarcinoma (LAC). There existed three types of alternatively spliced DDX39 variants (DDX39-L, -S and -SS), of which only DDX39-L contains all the motifs required for RNA helicase activity. RT-PCR analysis verified the increased expression of DDX39-L in LSCC, but not LAC, cultured cells compared with normal bronchial epithelial cells. A high sequence similarity to UAP56 and punctate nuclear localization pattern of DDX39-L suggest that it plays a role in RNA splicing/export. Recombinant DDX39-L binds RNA, hydrolyzes NTPs in an RNA-dependent manner and unwinds double strand RNA bidirectionally, proving that DDX39 is an RNA helicase. Overexpression of DDX39-L stimulates colony formation of HeLa cells, probably through elevation of a translational level, indicating the biological significance of DDX39 in cancer pathogenesis. Thus, DDX39 is a novel RNA helicase capable of promoting cancer cell growth and, thereby, can be a potential target for development of a therapeutic strategy for LSCC.

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

Cited by 51 publications

References 35 publications

HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target

HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target

HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis

DDX39, upregulated in lung squamous cell cancer, displays RNA helicase activities and promotes cancer cell growth

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