title: Hepsin inhibits CDK11p58 IRES activity by suppressing unr expression and eIF-2α phosphorylation in prostate cancer.
abstract: Hepsin is a type II transmembrane serine protease frequently overexpressed in prostate cancer (PCa). However, the role of hepsin in PCa remains unclear. In this study, we found that hepsin inhibited the internal ribosome entry site (IRES) activity and expression of CDK11p58, which is associated with cell cycle progression and pro-apoptotic signaling in PCa. Hepsin suppressed CDK11p58 IRES activity in PCa by modulating unr expression and eIF-2α phosphorylation. Further studies revealed that hepsin inhibited the expression of unr by directly binding to unr IRES element and suppressing its activity, and also repressed eIF-2α phosphorylation through down-regulating the expression and phosphorylation of general control non-derepressible-2 (GCN2). Taken together, our data suggest a novel role of hepsin in regulating CDK11p58 IRES activity, and imply that hepsin may act on the machinery of translation to modulate cell cycle progression and survival in PCa cells.
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Jianhao
authors.initials: J
authors.lastname: Peng
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: yuanyuanruan@fudan.edu.cn.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Gene Research Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D056743:Cyclin D3 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics*; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: C534696:CCND3 protein, human; C079950:CSDE1 protein, human; D056743:Cyclin D3; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D000067556:Internal Ribosome Entry Sites; D016601:RNA-Binding Proteins; D012697:Serine Endopeptidases; C055645:hepsin
keywords: CDK11p58; Hepsin; IRES; eIF-2α; unr