TIP49b, a Regulator of Activating Transcription Factor 2 Response to Stress and DNA Damage

Cho, Ssang-Goo; Bhoumik, Anindita; Broday, Limor; Ivanov, Vladimir N.; Rosenstein, Barry S.; Ronai, Ze’ev A.

doi:10.1128/mcb.21.24.8398-8413.2001

Cited by 72 publications

(75 citation statements)

References 70 publications

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“…9 Several publications have shown that RUVBL2 behaves as an antagonist of the transcriptional activity of the ␤-catenin-T-cell factor/lymphoid enhancer-binding factor complex. 9,15 Because ␤-catenin is considered an oncogene in HCC, these results appear counterintuitive. However, recently, RUVBL2 was also found to be required for the repressing effect of ␤-catenin on the transcription of the antimetastatic gene KAI-1, 36 which is frequently down-regulated in HCC.…”

Section: Discussionmentioning

confidence: 48%

“…Indeed, RUVBL2 has been found in supramolecular complexes that do not include ␤-catenin, 11 and ␤-catenin-independent functions of RUVBL2 have already been identified. 15 It is also noteworthy that RUVBL2 is required for the viability of yeast, 7,31,32 an organism devoid of ␤-catenin. In this context, 1 of the salient findings of this study was that in addition to its overexpression in HCC, RUVBL2 was also found in the cytoplasm of HCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Recently, it has been found that RUVBL2 is able to interact with ␤-catenin, resulting in altered T-cell factor/lymphoid enhancer-binding factormediated transcription. 9,15 RUVBL2 also interacts with a domain of cellular v-myc myelocytomatosis viral oncogene homolog of the manuscript (c-myc) required for oncogenic transformation, 8 and its expression is controlled by c-myc itself. 8,16 Given that ␤-catenin and c-myc are 2 key actors of liver carcinogenesis, our study was designed to assess the role of RUVBL2 in liver carcinogenesis.…”

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confidence: 99%

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Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma

et al. 2007

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Using a proteomic analysis of human hepatocellular carcinoma (HCC), we identified the overexpression in 4 tumors of RuvB-like 2 (RUVBL2), an ATPase and putative DNA helicase known to interact with ␤-catenin and cellular v-myc myelocytomatosis viral oncogene homolog (c-myc). RUVBL2 expression was further analyzed in tumors with quantitative reverse-transcription polymerase chain reaction analysis and immunohistochemistry; in addition, RUVBL2 expression in a HuH7 cell line was silenced by small interfering RNA or increased with a lentiviral vector. RUVBL2 messenger RNA overexpression was confirmed in 72 of 96 HCC cases, and it was associated with poorly differentiated tumors (P ‫؍‬ 0.02) and a poor prognosis (P ‫؍‬ 0.02) but not with ␤-catenin mutations or c-myc levels. Although RUVBL2 was strictly nuclear in normal hepatocytes, tumoral hepatocytes exhibited additional cytoplasmic staining. There was no mutation in the coding sequence of RUVBL2 in 10 sequenced cases. Silencing RUVBL2 in HuH7 HCC cells reduced cell growth (P < 0.001) and increased apoptosis, as shown by DNA fragmentation (P < 0.001) and caspase 3 activity (P < 0.005). This was associated with an increased expression of several proapoptotic genes and with an increased conformational activation of Bak-1 and Bax. On the other hand, HuH7 cells with an overexpression of RUVBL2 grew better in soft agar (P < 0.03), had increased resistance to C2 ceramide-induced apoptosis (P < 0.001), and gave rise to significantly larger tumors when injected into immunodeficient Rag2/␥c mice (P ‫؍‬ 0.016). Conclusion: RUVBL2 is overexpressed in a large majority of HCCs. RUVBL2 overexpression enhances tumorigenicity, and RUVBL2 is required for tumor cell viability. These results argue for a major role of RUVBL2 in liver carcinogenesis.

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma

et al. 2007

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“…Furthermore, treatment with TBEP altered the expression of proteins related to DNA damage and caused an increase in the number of apoptotic cells in the tail region. Previous studies demonstrated that RuvB-like (RBL) proteins play a key role in modulating the response to DNA damage (Cho et al, 2001;Kakugawa et al, 2009), and exposure to TBEP significantly downregulated the expression of Rbl2 in this study. Thus, this downregulation may inhibit the biological response to DNA damage, which was supported by downregulated expression of proteins related to DNA repair (DEAH (Asp-Glu-Ala-His) box polypeptide 15, and protein BCCIP homolog).…”

Section: Discussionmentioning

confidence: 62%

Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate

Han

Wang

et al. 2014

Aquatic Toxicology

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“…With regard to Reptin, the Walker B mutant D299N was not able to complement the effect of the loss of endogenous Reptin on the amount of PIKK proteins in HEK293 cells (7), suggesting that the ATPase activity of Reptin is indeed required for the regulation of PIKK levels. However, the same mutant was as efficient as wild-type (WT) Reptin for the repression of the influenza A virus polymerase (18) or of the transcriptional activity of ATF2 (19). In the latter case, the C-terminus part of Reptin lacking both Walker domains was almost as efficient as the complete protein.…”

Section: Introductionmentioning

confidence: 90%

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

Grigoletto

Neaud

Allain-Courtois

et al. 2013

Molecular Cancer Research

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Reptin is overexpressed in most human hepatocellular carcinomas. Reptin is involved in chromatin remodeling, transcription regulation, or supramolecular complexes assembly. Its silencing leads to growth arrest and apoptosis in cultured hepatocellular carcinoma cells and stops hepatocellular carcinoma progression in xenografts. Reptin has an ATPase activity linked to Walker A and B domains. It is unclear whether every Reptin function depends on its ATPase activity. Here, we expressed Walker B ATPase-dead mutants (D299N or E300G) in hepatocellular carcinoma cells in the presence of endogenous Reptin. Then, we silenced endogenous Reptin and substituted it with siRNA-resistant wild-type (WT) or Flag-Reptin mutants. There was a significant decrease in cell growth when expressing either mutant in the presence of endogenous Reptin, revealing a dominant negative effect of the ATPase dead mutants on hepatocellular carcinoma cell growth. Substitution of endogenous Reptin by WT Flag-Reptin rescued cell growth of HuH7. On the other hand, substitution by Flag-Reptin D299N or E300G led to cell growth arrest. Similar results were seen with Hep3B cells. Reptin silencing in HuH7 cells led to an increased apoptotic cell death, which was prevented by WT Flag-Reptin but not by the D299N mutant. These data show that Reptin functions relevant for cancer are dependent on its ATPase activity, and suggest that antagonists of Reptin

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TIP49b, a Regulator of Activating Transcription Factor 2 Response to Stress and DNA Damage

Cited by 72 publications

References 70 publications

Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma

Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma

Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate

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

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