Phosphorylation of threonine 204 of DEAD-box RNA helicase DDX3 by cyclin B/cdc2 in vitro

Sekiguchi, Toshio; Kurihara, Y.; Fukumura, Junko

doi:10.1016/j.bbrc.2007.03.038

Cited by 26 publications

(16 citation statements)

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“…For example, inactivation of DDX3 by HBx and HCV core proteins may promote tumor growth via suppression of p21 transcription through the p53-independent pathway (20,21). In addition, inactivation of DDX3 by phosphorylation at Thr204 by the cyclin B/ cdc2 complex halts HeLa cells in the S phase through reduced cyclin A expression (22). However, the role of DDX3 in HPV-associated tumorigenesis remains to be elucidated, especially with respect to lung tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Reduced p21WAF1/CIP1 via Alteration of p53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus–Associated Lung Cancer

Liu

Wang

et al. 2011

Clinical Cancer Research

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Purpose: DDX3 alteration has been shown to participate in hepatocellular tumorigenesis via p21 WAF1/CIP1 (p21) deregulation. We observed that DDX3 and p21 expression in lung tumors was negatively associated with E6 expression. Therefore, the aim of this study was to clarify whether deregulation of p21 by DDX3 via an E6-inactivated p53 pathway would enhance tumor progression in HPV-associated lung cancers. Experimental Design: Real-time PCR, luciferase assays, immunoprecipitation, and chromatin immunoprecipitation (ChIP) were performed to determine whether DDX3 was regulated by p53 to synergistically enhance p21 transcriptional activity. Cell proliferation was examined by cell counting and colony formation assays. DDX3 and p21 expression were evaluated in 138 lung tumors by real-time PCR and immunohistochemistry. The prognostic value of p21 expression on relapse-free survival (RFS) was analyzed by Kaplan-Meier analysis.Results: Real-time PCR, luciferase assays, and ChIP assays indicated that three putative p53 binding sites, located at À1,080/À1,070, À695/À685, and À283/À273 on the DDX3 promoter, were required for DDX3 transcription. DDX3 deregulation by the E6-inactivated p53 pathway could promote cell proliferation and the ability to form colonies via reduced Sp1 binding activity on the p21 promoter. Among tumors, p21 expression was positively associated with DDX3 expression and negatively related with E6 expression, particularly in early-stage (I þ II) tumors. Interestingly, low p21 expression was associated with a poor RFS in early-stage lung cancer.Conclusion: The reduction of p21 by the alteration of the p53-DDX3 pathway plays an essential role in early-stage HPV-associated lung tumorigenesis and is correlated with poor RFS of lung cancer patients. Clin Cancer Res; 17(7); 1895-905. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Reduced p21WAF1/CIP1 via Alteration of p53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus–Associated Lung Cancer

Liu

Wang

et al. 2011

Clinical Cancer Research

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“…In addition, the functional impact of posttranslational modifications on these events will need to be investigated; DDX3, for example, is phosphorylated at a Thr residue within the Q-motif, which abrogates its activity 140 . Collectively, these are significant challenges, but the impressive progress made over the past few years is reason to be optimistic that we will see a rapidly continuing increase in our understanding of how DEAD box proteins function and of their central roles in cellular RNA metabolism.…”

Section: Future Challenges and Perspectivementioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

918

1,069

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Nearly all aspects of RNA metabolism, from transcription and translation to mRNA decay, involve RNA helicases, which are enzymes that use ATP to bind or remodel RNA and RNA-protein complexes (ribonucleoprotein (RNP) complexes) 1 . RNA helicases are found in all three domains of life, and many viruses also encode one or more of these proteins 2,3 . Together with the structurally related DNA helicases that function in replication, recombination and repair, the RNA helicases are classified into superfamilies and families, based on sequence and structural features 3,4 . DEAD box proteins form the largest helicase family, with 37 members in humans and 26 in Saccharomyces cerevisiae 3 , and are characterized by the presence of an Asp-Glu-Ala-Asp (DEAD) motif.DEAD box helicases have central and, in many cases, essential physiological roles in cellular RNA metabolism 5 (FIG. 1). The proteins generally function as part of larger multicomponent assemblies, such as the spliceosom e or the eukaryotic translation initiation machinery 6 . Mutations and deregulation of several DEAD box proteins have been linked to disease states, including cancer 7 . Although all DEAD box proteins contain a structurally highly conserved core with conserved ATP-binding and RNA-binding sites, different proteins have been associated with diverse and seemingly unrelated functions, including the disassembly of RNPs, chaperoning during RNA folding and even stabil ization of protein complexes on RNA 5,6 . How these highly conserved proteins fulfil such an array of different functions has been a long-standing question.Research has now started to illuminate the molecular basis for this functional diversity. In this Review, we summarize how structural data, together with biochemical and biophysical studies, have revealed unexpected modes by which these proteins function. We also discuss how novel molecular and cell biological approaches have better defined the cellular roles of DEAD box helicases. We outline our current view on common structural and mechan istic themes that have emerged, and on physical models of how these 'unusual' RNA helicases work.Structures of DEAD box RNA helicases A number of structural studies have universally shown that members of the DEAD box family contain a highly conserved helicase core that harbours the binding sites for ATP and RNA 3,4,8 . The core is surrounded by variable auxiliary domains, which are thought to be critical for the diverse functions of these enzymes.Structure of the helicase core. DEAD box proteins belong to helicase superfamily 2 (SF2) 2 . Similarly to all SF2 helicases, DEAD box proteins are built around a highly conserved helicase core of two virtually identical domains that resemble the bacterial recombination protein recombinase A (RecA) 3,4,8 (FIG. 2a,b). Within this helicase core, at least 12 characteristic sequence motifs are located at conserved positions (FIG. 2a,b). Some of these motifs are conserved across the entire SF2 family, whereas others are found only in the DEAD box family 3 ....

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“…However, in another study, DDX3 in hepatocellular carcinoma cell lines was shown to transcriptionally upregulate the tumor suppressor molecule, p21, thus decreasing cell proliferation (Chang et al, 2006;Chao et al, 2006). Also, DDX3 has been shown to be inactivated in HeLa cells during mitosis via the phosphorylation of Threonine 204 by the cyclinB/cdc2 complex (Sekiguchi et al, 2007). Thus, the role of DDX3 in cancer biogenesis appears to be divergent and tumor type-dependent.…”

Section: Introductionmentioning

confidence: 98%

Oncogenic role of DDX3 in breast cancer biogenesis

et al. 2008

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Benzo [a]pyrene diol epoxide (BPDE), the active metabolite of benzo [a]pyrene present in tobacco smoke, is a major cancer-causing compound. To evaluate the effects of BPDE on human breast epithelial cells, we exposed an immortalized human breast cell line, MCF 10A, to BPDE and characterized the gene expression pattern. Of the differential genes expressed, we found consistent activation of DDX3, a member of the DEAD box RNA helicase family. Overexpression of DDX3 in MCF 10A cells induced an epithelial-mesenchymal-like transformation, exhibited increased motility and invasive properties, and formed colonies in soft-agar assays. Besides the altered phenotype, MCF 10A-DDX3 cells repressed E-cadherin expression as demonstrated by both immunoblots and by E-cadherin promoter-reporter assays. In addition, an in vivo association of DDX3 and the E-cadherin promoter was demonstrated by chromatin immunoprecipitation assays. Collectively, these results demonstrate that the activation of DDX3 by BPDE, can promote growth, proliferation and neoplastic transformation of breast epithelial cells.

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Phosphorylation of threonine 204 of DEAD-box RNA helicase DDX3 by cyclin B/cdc2 in vitro

Cited by 26 publications

References 27 publications

Reduced p21WAF1/CIP1 via Alteration of p53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus–Associated Lung Cancer

Reduced p21WAF1/CIP1 via Alteration of p53-DDX3 Pathway Is Associated with Poor Relapse-Free Survival in Early-Stage Human Papillomavirus–Associated Lung Cancer

From unwinding to clamping — the DEAD box RNA helicase family

Oncogenic role of DDX3 in breast cancer biogenesis

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