The ATPase Activity of Reptin Is Required for Its Effects on Tumor Cell Growth and Viability in Hepatocellular Carcinoma

Grigoletto, Aude; Neaud, Véronique; Allain-Courtois, Nathalie; Lestienne, Patrick; Rosenbaum, Jean

doi:10.1158/1541-7786.mcr-12-0455

Cited by 29 publications

(32 citation statements)

References 27 publications

(51 reference statements)

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“…For many ATPases such as AAA þ ATPases, Hsp90, and Dnd, the ATPase activity is vital for their physiologic functions (27,41,42). To identify whether an intact endostatin ATPase activity is required for its antiangiogenic effects, we assessed the inhibitory effects of endostatin and its mutants on endothelial cell proliferation, migration, tube formation, and adhesion.…”

Section: The Atpase Activity Of Endostatin Mediates Its Effects On Enmentioning

confidence: 99%

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Wang

Liu

et al. 2015

Molecular Cancer Therapeutics

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Endostatin is an endogenous angiogenesis inhibitor with broad-spectrum antitumor activities. Although the molecular mechanisms of endostatin have been extensively explored, the intrinsic biochemical characteristics of endostatin are not completely understood. Here, we revealed for the first time that endostatin embedded novel ATPase activity. Moreover, mutagenesis study showed that the ATPase activity of endostatin mutants positively correlated with effects on endothelial cell activities and tumor growth. E-M, an endostatin mutant with higher ATPase activity than that of wild-type (WT) endostatin, significantly increased endostatin-mediated inhibitory effects on endothelial cell proliferation, migration, tube formation, and adhesion. In vivo study showed that E-M displayed enhanced antitumor effects compared with WT. On the other hand, K96A, K96R, and E176A, endostatin mutants with lower ATPase activities than that of WT, showed reduced or comparable effects on targeting both in vitro endothelial cell activities and in vivo tumor angiogenesis and tumor growth. Furthermore, endostatin and its mutants exhibited distinct abilities in regulations of gene expression (Id1, Id3), cell signaling (Erk, p38, and Src phosphorylation), and intracellular ATP levels. Collectively, our study demonstrates that endostatin has novel ATPase activity, which mediates its antiangiogenic and antitumor activities, suggesting that construction of endostatin analogues with high ATPase activity may provide a new direction for the development of more potent antiangiogenic drugs.

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Section: The Atpase Activity Of Endostatin Mediates Its Effects On Enmentioning

confidence: 99%

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Wang

Liu

et al. 2015

Molecular Cancer Therapeutics

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“…Rosenbaum’s group now shows that the ATPase activity of Reptin is required for sustaining tumor cell growth, suggesting that Reptin could be a viable drug target for cancer therapy (37). In collaboration with Michel Laguerre’s group (Institut Européen de Chimie et de Biologie, Pessac, France), Patrick Lestienne, from the Rosenbaum group, presented small molecule inhibitors of Pontin’s ATPase activity identified through in silico modeling and in vitro testing (38).…”

Section: Pathophysiology and Therapeutic Targetingmentioning

confidence: 99%

The Emergence of the Conserved AAA+ ATPases Pontin and Reptin on the Signaling Landscape Meeting Information: The First International Workshop on Pontin (RUVBL1) and Reptin (RUVBL2) took place at the European Institute for Chemistry and Biology in Pessac, France, 16 to 19 October 2012.

et al. 2013

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Pontin (also known as RUVBL1 and RVB1) and Reptin (also called RUVBL2 and RVB2) are related members of the large AAA+ (adenosine triphosphatase associated with diverse cellular activities) superfamily of conserved proteins. Various cellular functions depend on Pontin and Reptin, mostly because of their functions in the assembly of protein complexes that play a role in the regulation of cellular energetic metabolism, transcription, chromatin remodeling, and the DNA damage response. Little is known, though, about the interconnections between these multiple functions, how the relevant signaling pathways are regulated, whether the interconnections are affected in human disease, and whether components of these pathways are suitable targets for therapeutic intervention. The First International Workshop on Pontin (RUVBL1) and Reptin (RUVBL2), held between 16 and 19 October 2012, discussed the nature of the oligomeric organization of these proteins, their structures, their roles as partners in various protein complexes, and their involvement in cellular regulation, signaling, and pathophysiology, as well as their potential for therapeutic targeting. A major outcome of the meeting was a general consensus that most functions of Pontin and Reptin are related to their roles as chaperones or adaptor proteins that are important for the assembly and function of large signaling protein complexes.

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“…For example, ATPase activities of both proteins are required for regulation of heart growth in zebrafish embryos [33] and c‐Myc‐induced cell transformation [20]. It is also been shown that the ATPase activity of Reptin is required for tumor cell growth in HCC [26]. On the other hand, the ATPase activity is dispensable for some of Reptin functions such as repression of the influenza A virus polymerase [34] and of the transcriptional activity of ATF2 [23].…”

Section: Discussionmentioning

confidence: 99%

Reptin physically interacts with p65 and represses NF‐κB activation

2015

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a b s t r a c tReptin and Pontin belong to the AAA+ ATPase family of DNA helicases. Both proteins are present in several chromatin-remodeling machineries and are involved in transcriptional regulation, DNA repair, and telomerase activity, but they also function independently from each other. Here we report the identification of p65 as an interacting partner of Reptin. Using reporter gene assays, we show Reptin inhibits NF-jB transactivation after TNFa stimulation. Reptin is mainly localized in the cytoplasm and impedes NF-jB activation by inhibiting IjB-a degradation and restraining p65 nuclear translocation. These results reveal a novel mechanism for the control of NF-jB pathway by cytoplasmic Reptin.

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The ATPase Activity of Reptin Is Required for Its Effects on Tumor Cell Growth and Viability in Hepatocellular Carcinoma

Cited by 29 publications

References 27 publications

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

Endostatin Has ATPase Activity, Which Mediates Its Antiangiogenic and Antitumor Activities

The Emergence of the Conserved AAA+ ATPases Pontin and Reptin on the Signaling Landscape Meeting Information: The First International Workshop on Pontin (RUVBL1) and Reptin (RUVBL2) took place at the European Institute for Chemistry and Biology in Pessac, France, 16 to 19 October 2012.

Reptin physically interacts with p65 and represses NF‐κB activation

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