作者: Kong, Xiangjun ; Gaboury, Louis ; Miller, Lance D. ; Zeng, Qi ; Thike, Aye Aye ; Sethi, Gautam ; Tergaonkar, Vinay ; Wu, Zhengsheng ; Lobie, Peter E. ; Ong, Hooi Tin ; Lim, Chwee Teck ; Mendoz, Earnest ; Lee, Moon Hee ; Shin, Eun Myoung ; Goh, Jen Nee ; Lim, Yoon Pin ; Sun, Wei ; Tan, Puay Hoon ; Hay, Hui Sin ; Hui, Kam Man ; Goh, Boon Cher ; Sen, Yin Ping ; Zhu, Tao ; Yip, George Wai-Cheong ; Miyamoto, Shigeki ; Yousef, Einas M. ; Tan, Tuan Zea ; Thiery, Jean Paul ; Kumar, Alan Prem ; Lim, See Wee ; Lee, Martin B. ; Salto-Tellez, Manuel ; Yap, Celestial T. ; Tan, Patrick

Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β-activated kinase-1 (TAK1) phosphorylation of NF-κB-activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB-mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.

2005-03-01·Molecular and Cellular Biology3区 · 生物学

The DEAD-Box Protein DP103 (Ddx20 or Gemin-3) Represses Orphan Nuclear Receptor Activity via SUMO Modification

3区 · 生物学

Article

作者: Lee, Martin B. ; Lebedeva, Lioudmila A. ; Desclozeaux, Marion ; Wadekar, Subhagya A. ; Suzawa, Miyuki ; Ingraham, Holly A.

ABSTRACTStructural analysis of nuclear receptor subfamily V orphan nuclear receptors suggests that ligand-independent mechanisms must regulate this subclass of receptors. Here, we report that steroidogenic factor 1 (SF-1) and liver receptor homolog 1 are repressed via posttranslational SUMO modification at conserved lysines within the hinge domain. Indeed, mutating these lysines or adding the SUMO isopeptidase SENP1 dramatically increased both native and Gal4-chimera receptor activities. The mechanism by which SUMO conjugation attenuates SF-1 activity was found to be largely histone deacetylase independent and was unaffected by the AF2 corepressor Dax1. Instead, our data suggest that SUMO-mediated repression involves direct interaction of the DEAD-box protein DP103 with sumoylated SF-1. Of potential E3-SUMO ligase candidates, PIASy and PIASxα strongly promoted SF-1 sumoylation, and addition of DP103 enhanced both PIAS-dependent receptor sumoylation and SF-1 relocalization to discrete nuclear bodies. Taken together, we propose that DEAD-box RNA helicases are directly coupled to transcriptional repression by protein sumoylation.

100 项与 DP-103 相关的药物交易

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