DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Chang, Phei‐Lang; Chi, C. W.; Chau, Gar Yang; Li, F. Y.; Tsai, Y. H.; Wu, Jin; Lee, Yan-Hwa Wu

doi:10.1038/sj.onc.1209239

Cited by 129 publications

(149 citation statements)

References 76 publications

(79 reference statements)

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“…Presumably, the biological roles of DDX3 may overlap with other eIF4E-binding proteins to provide a backup or compensatory mechanism. As shown in our recent work, DDX3 exerts an inhibitory effect on cell growth, whereas a genetic knockdown of DDX3 results in an enhancement of cell proliferation (Chang et al, 2006;Chao et al, 2006). This cell growth-suppressive property of DDX3 is linked to its transactivation ability on p21 waf1/cip1 promoter through physical interaction with Sp1 (Chao et al, 2006).…”

Section: Ddx3 Interacts With Eif4e and Regulates Translationmentioning

confidence: 57%

“…The DDX3-eIF4E interaction is required for the tumor growth suppressive ability of DDX3 Our previous studies have demonstrated that the DDX3-mediated upregulation of p21 waf1/cip1 promoter activity could account for the tumor suppressor function of DDX3 (Chang et al, 2006;Chao et al, 2006). Based on this, we extended our studies to address whether the DDX3-eIF4E interaction is required for the aforementioned property of DDX3.…”

Section: Gakdyrqssg Ag-ssfgssr Ggrs----sg Hggsr----------gfggg -Yggfymentioning

confidence: 72%

“…More recently, we demonstrated that DDX3 harbors tumor-growth suppressive ability and can modulate the transcriptional activity of the p21 waf1/cip1 promoter through physical interaction with Sp1 (Chao et al, 2006). Furthermore, we have also reported that DDX3 is inactivated through deregulation of expression or nuclear exclusion in tumor cells (Chang et al, 2006;Chao et al, 2006). These findings suggest a regulatory role for DDX3 in cell growth and tumorigenesis.…”

mentioning

confidence: 76%

“…This cell growth-suppressive property of DDX3 is linked to its transactivation ability on p21 waf1/cip1 promoter through physical interaction with Sp1 (Chao et al, 2006). Furthermore, a significant downregulation of DDX3 expression has been observed in hepatoma specimens (Chang et al, 2006;Chao et al, 2006). All these features suggest that DDX3 acts as a tumor suppressor.…”

Section: Ddx3 Interacts With Eif4e and Regulates Translationmentioning

confidence: 96%

“…Presumably, this DDX3-mediated stimulatory effect on IRES-dependent translation is through sequestration of the available eIF4E, which may augment HCV viral replication or selectively stimulate IRES-directed translation of cellular transcripts. Most importantly, this eIF4E-binding ability or translation regulatory effect of DDX3 is required for the tumor growth suppressor function of DDX3 that has been reported recently (Chang et al, 2006;Chao et al, 2006).…”

mentioning

confidence: 91%

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Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Shih¹,

Tsai²,

Chao³

et al. 2007

Oncogene

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DDX3 is a human RNA helicase with plethoric functions. Our previous studies have indicated that DDX3 is a transcriptional regulator and functions as a tumor suppressor. In this study, we use a bicistronic reporter to demonstrate that DDX3 specifically represses cap-dependent translation but enhances hepatitis C virus internal ribosome entry site-mediated translation in vivo in a helicase activity-independent manner. To elucidate how DDX3 modulates translation, we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. Point mutations within the consensus eIF4E-binding motif in DDX3 impair its ability to bind eIF4E and result in a loss of DDX3's regulatory effects on translation. All these features together indicate that DDX3 is a new member of the eIF4E inhibitory proteins involved in translation initiation regulation. Most importantly, this DDX3-mediated translation regulation also confers the tumor suppressor function on DDX3. Altogether, this study demonstrates regulatory roles and action mechanisms for DDX3 in translation, cell growth and likely viral replication.

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Section: Ddx3 Interacts With Eif4e and Regulates Translationmentioning

confidence: 57%

Section: Gakdyrqssg Ag-ssfgssr Ggrs----sg Hggsr----------gfggg -Yggfymentioning

confidence: 72%

mentioning

confidence: 76%

Section: Ddx3 Interacts With Eif4e and Regulates Translationmentioning

confidence: 96%

mentioning

confidence: 91%

See 3 more Smart Citations

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Shih¹,

Tsai²,

Chao³

et al. 2007

Oncogene

Self Cite

158

198

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The DEAD‐box RNA helicase DDX3 interacts with DDX5, co‐localizes with it in the cytoplasm during the G₂/M phase of the cycle, and affects its shuttling during mRNP export

Choi

Lee

2012

J of Cellular Biochemistry

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DDX3 is involved in RNA transport, translational control, proliferation of RNA viruses, and cancer progression. From yeast two-hybrid screening using the C-terminal region of DDX3 as a bait, the DEAD-box RNA helicase DDX5 was cloned. In immunofluorescence analysis, DDX3 and DDX5 were mainly co-localized in the cytoplasm. Interestingly, cytoplasmic levels of DDX5 increased in the G(2) /M phase and consequently protein-protein interaction also increased in the cytoplasmic fraction. DDX3 was highly phosphorylated at its serine, threonine, and tyrosine residues in the steady state, but not phosphorylated at the serine residue(s) in the G(2) /M phase. DDX5 was less phosphorylated in the G(1) /S phase; however, it was highly phosphorylated at serine, threonine, and tyrosine residues in the G(2) /M phase. PP2A treatment of the cytoplasmic lysate from G(2) /M phase cells positively affected the interaction between DDX3 and DDX5, whereas, PTP1B treatment did not. In an analysis involving recombinant His-DDX3 and His-DDX5, PP2A pretreatment of His-DDX5 increased the interaction with endogenous DDX3, and vice versa. Furthermore, the results of GST pull-down experiments support the conclusion that dephosphorylation of serine and/or threonine residues in both proteins enhanced protein-protein interactions. UV cross-linking experiments showed that DDX3 and DDX5 are involved in mRNP export. Additionally, DDX3 knockdown blocked the shuttling of DDX5 to the nucleus. These data demonstrate a novel interaction between DDX3 and DDX5 through the phosphorylation of both proteins, especially in the G(2) /M phase, and suggest a novel combined mechanism of action, involving RNP remodeling and splicing, for DEAD-box RNA helicases involved in mRNP export.

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Human DEAD‐box ATPase DDX3 shows a relaxed nucleoside substrate specificity

et al. 2007

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Human DDX3 (hDDX3) is a DEAD-box protein shown to possess RNA-unwinding and adenosine triphosphatase (ATPase) activities. The hDDX3 protein has been implicated in nuclear mRNA export, cell growth control, and cancer progression. In addition, a role of this protein in the replication of human immunodeficiency virus Type 1 and in the pathogenesis of hepatitis C virus has been recently proposed. Its enzymological properties, however, are largely unknown. In this work, we characterized its ATPase activity. We show that hDDX3 ATPase activity is stimulated by various ribo- and deoxynucleic acids. Comparative analysis with different nucleoside triphosphate analogs showed that the hDDX3 ATPase couples high catalytic efficiency to a rather relaxed substrate specificity, both in terms of base selection and sugar selection. In addition, its ability to recognize the L-stereoisomers of both 3' deoxy- and 2',3' dideoxy-ribose, points to a relaxed stereoselectivity. On the basis of these results, we hypothesize the presence of structural determinants on both the base and the sugar moieties, critical for nucleoside binding to the enzyme. Our results expand the knowledge about the DEAD-box RNA helicases in general and can be used for rational design of selective inhibitors of hDDX3, to be tested as potential antitumor and antiviral agents.

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DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Cited by 129 publications

References 76 publications

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

The DEAD‐box RNA helicase DDX3 interacts with DDX5, co‐localizes with it in the cytoplasm during the G₂/M phase of the cycle, and affects its shuttling during mRNP export

Human DEAD‐box ATPase DDX3 shows a relaxed nucleoside substrate specificity

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DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Cited by 129 publications

References 76 publications

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein

The DEAD‐box RNA helicase DDX3 interacts with DDX5, co‐localizes with it in the cytoplasm during the G2/M phase of the cycle, and affects its shuttling during mRNP export

Human DEAD‐box ATPase DDX3 shows a relaxed nucleoside substrate specificity

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The DEAD‐box RNA helicase DDX3 interacts with DDX5, co‐localizes with it in the cytoplasm during the G₂/M phase of the cycle, and affects its shuttling during mRNP export