The DEAD box protein Ddx42p modulates the function of ASPP2, a stimulator of apoptosis

Uhlmann‐Schiffler, Heike; Kiermayer, Simone; Stahl, Hans

doi:10.1038/onc.2009.75

Cited by 25 publications

(24 citation statements)

References 36 publications

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“…DDX42 is a putative ATP-dependent RNA helicase implicated in cellular growth and apoptosis. It is a major apoptosis inducer known to enhance p53 transactivation of proapoptotic genes [23]. In this study, DDX42 was approximately 4.5-fold upregulated.…”

Section: Discussionmentioning

confidence: 81%

“…The expression levels of apoptosis associated factors, such as ATP-dependent RNA helicase (DDX42), Bcl-2, p53, low-density lipoprotein (LDL), apo B and matrix metalloproteinases, changed during FGR development [6,23,24,25,26,27,28]. However, thus far, no large-scale proteomic analyses have been used to investigate the regulatory factors involved in the placenta of pregnancies with FGR.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Miao

Chen

Wang

et al. 2014

Cell Physiol Biochem

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Background: Fetal growth restriction (FGR) is the main cause of intrauterine fetal death and the second leading cause of death in the neonatal period. A large body of evidence suggests that FGR may be associated with the placenta, although its etiology and pathogenesis remain to be fully elucidated. Methods and Results: To better understand the molecular mechanisms underlying the pathological development of the placenta in FGR, we used tandem mass tags (TMTs) to construct a large-scale comparative proteomic profile of human placentas from normal and FGR pregnancies. A total of 1,198 kinds of proteins were identified in the control and FGR placentas, of which 95 were differentially expressed between two groups. Ingenuity Pathway Analysis (IPA) was used to organize these differentially expressed proteins into networks of interacting proteins and to identify the modules of functionally related proteins. Western blotting was used to verify the expression patterns of several randomly selected proteins. Conclusion: The placentas of women with FGR displayed significant proteome differences compared with normal pregnancy. The results indicate that a variety of mechanisms and proteins may contribute to the development of FGR. Further studies and validations are required to elucidate the exact roles of these proteins in FGR pathogenesis.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Miao

Chen

Wang

et al. 2014

Cell Physiol Biochem

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“…S2B). Although there is no clear consensus as to the exact localization of ASPP2 (27,28), a recent study described the targeting of ASPP2 to tight junctions (29). Because full-length CagA is also found close to the plasma membrane and junctional complexes, CagA likely recruits ASPP2 to form a complex near the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

Buti

Spooner

Veen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

212

166

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Type I strains of Helicobacter pylori (Hp) possess a pathogenicity island, cag , that encodes the effector protein cytotoxin-associated gene A (CagA) and a type four secretion system. After translocation into the host cell, CagA affects cell shape, increases cell motility, abrogates junctional activity, and promotes an epithelial to mesenchymal transition-like phenotype. Transgenic expression of CagA enhances gastrointestinal and intestinal carcinomas as well as myeloid and B-cell lymphomas in mice, but the mechanism of the induced cancer formation is not fully understood. Here, we show that CagA subverts the tumor suppressor function of apoptosis-stimulating protein of p53 (ASPP2). Delivery of CagA inside the host results in its association with ASPP2. After this interaction, ASPP2 recruits its natural target p53 and inhibits its apoptotic function. CagA leads to enhanced degradation of p53 and thereby, down-regulates its activity in an ASPP2-dependent manner. Finally, Hp-infected cells treated with the p53-activating drug Doxorubicin are more resistant to apoptosis than uninfected cells, an effect that requires ASPP2. The interaction between CagA and ASPP2 and the consequent degradation of p53 are examples of a bacterial protein that subverts the p53 tumor suppressor pathway in a manner similar to DNA tumor viruses. This finding may contribute to the understanding of the increased risk of gastric cancer in patients infected with Hp CagA+ strains.

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“…39 Although the molecular mechanisms underlying these attenuated cellular damage-response thresholds remain to be clarified, it seems that cell type and context are important determinants of when/if ASPP2 engages different biologic programs that ultimately inhibit cell growth and promote tumor suppression. There is ample hypothesis-generating in vitro evidence in the literature suggesting that ASPP2 (and/or isoforms) also modulates expression of cell cycle-regulating genes, perturbs cell cycle progression, binds and modulates other proteins, or is regulated by pathways involved in diverse cellular functions 7,[9][10][11][12][13][14][15][16][17][18][19][20]26,42,43 (Table 1).…”

Section: Aspp2 Is a Tumor Suppressormentioning

confidence: 99%

“…9 Nevertheless, the caveats of overexpression made it challenging to fully appreciate the significance of these observations. The in vitro binding promiscuity of the 53BP2 C-terminal domain has resulted in a number of reports describing its interaction with a variety of proteins 7,[9][10][11][12][13][14][15][16][17][18][19][20] (Table 1) be an important mechanism for suppressing ASPP2 expression. 34,35 Interestingly, single nucleotide polymorphisms (SNPs) at the TP53BP2 locus are associated with gastric cancer susceptibility.…”

Section: Introductionmentioning

confidence: 99%

New insights into the expanding complexity of the tumor suppressor ASPP2

Kampa¹,

Bonin

Lopez³

2009

Cell Cycle

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Apoptosis Stimulating Protein of p53-2, ASPP2, aka 53BP2L, (encoded by TP53BP2) is a pro-apoptotic member of a family of p53 binding proteins. ASPP2 expression is frequently suppressed in human cancers and numerous studies have consistently demonstrated that ASPP2 inhibits cell growth as well as stimulates apoptosis-at least in part through a p53-mediated pathway. Two independent mouse models have shown that ASPP2 is a haplo-insufficient tumor suppressor and underscore the importance of the role of ASPP2 in human cancer. However, mounting evidence suggests that the mechanism(s) of action for ASPP2 are complex and likely extend beyond stimulation of apoptotic programs. Data highlighting this expanding spectrum of potential ASPP2-mediated pathways is summarized along with new results from recent in vivo models suggesting new avenues for investigation.

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The DEAD box protein Ddx42p modulates the function of ASPP2, a stimulator of apoptosis

Cited by 25 publications

References 36 publications

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Comparative Proteomic Profile of the Human Placenta in Normal and Fetal Growth Restriction Subjects

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

New insights into the expanding complexity of the tumor suppressor ASPP2

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