title: Generation of a novel proform of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein that can be reactivated by matrix metalloproteinases.
abstract: TRAIL has been suggested to induce the cell death in various tumor cells but not in normal cells; however, several studies have provided the evidence that TRAIL can induce the cell death in some normal cells including human normal hepatocytes, suggesting that TRAIL may show hepatic toxicity in human. In this study, we designed a pro-form of TRAIL (sTRAIL:IL-18) in that soluble TRAIL (sTRAIL) is fused to IL-18, and a matrix metalloproteinases (MMPs) cleavage site is introduced at the connecting site. We showed that sTRAIL:IL-18 has significantly diminished the killing activity in HeLa cells but regains the activity by releasing the free sTRAIL through MMP-2-mediated cleavage. In addition, the killing activity of sTRAIL:IL-18 was significantly increased in HeLa cells when active MMP-2 was produced by TNF-alpha. Taken together, the data suggested that the sTRAIL:IL-18 can be reactivated at the specialized areas where MMPs are pathologically produced.
authors.affiliation: Department of Biochemistry, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju 501-759, Republic of Korea.
authors.forename: Jin Na
authors.initials: JN
authors.lastname: Shin
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Jong Hee
authors.initials: JH
authors.lastname: Cha
authors.forename: Jae Yoon
authors.initials: JY
authors.lastname: Park
authors.forename: Byung Rai
authors.initials: BR
authors.lastname: Lee
authors.forename: Sun-Ah
authors.initials: SA
authors.lastname: Jung
authors.forename: Seung-Taek
authors.initials: ST
authors.lastname: Lee
authors.forename: Cheol-Won
authors.initials: CW
authors.lastname: Yun
authors.forename: Dai-Wu
authors.initials: DW
authors.lastname: Seol
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018076:DNA, Complementary; D020382:Interleukin-18; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2