Dominant-Negative Lox-1 Blocks Homodimerization of Wild-Type Lox-1–Induced Cell Proliferation Through Extracellular Signal Regulated Kinase 1/2 Activation

DOI Web Site 被引用文献8件
  • Hiroyuki Tanigawa
    From the Department of Cardiology (H.T., S.M., Y.M., M.F., K.S.), Fukuoka University Hospital, Fukuoka, Japan, and Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.
  • Shin-ichiro Miura
    From the Department of Cardiology (H.T., S.M., Y.M., M.F., K.S.), Fukuoka University Hospital, Fukuoka, Japan, and Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.
  • Yoshino Matsuo
    From the Department of Cardiology (H.T., S.M., Y.M., M.F., K.S.), Fukuoka University Hospital, Fukuoka, Japan, and Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.
  • Masahiro Fujino
    From the Department of Cardiology (H.T., S.M., Y.M., M.F., K.S.), Fukuoka University Hospital, Fukuoka, Japan, and Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.
  • Tatsuya Sawamura
    From the Department of Cardiology (H.T., S.M., Y.M., M.F., K.S.), Fukuoka University Hospital, Fukuoka, Japan, and Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.
  • Keijiro Saku
    From the Department of Cardiology (H.T., S.M., Y.M., M.F., K.S.), Fukuoka University Hospital, Fukuoka, Japan, and Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.

抄録

<jats:p> C-type lectin-like oxidized low-density lipoprotein (Ox-LDL) receptor-1 (Lox-1) belongs to the same family as natural killer cell receptors Ly49A and CD94 and functionally undergoes dimerization. Although Lys <jats:sup>262</jats:sup> and Lys <jats:sup>263</jats:sup> in the C terminus of bovine (b)Lox-1 play an important role in the uptake of Ox-LDL, mutation of these residues has not been suggested to be a potential source of the dominant-negative property. We hypothesize that dominant-negative human (h)Lox-1 forms a heterodimer with Lox-1–wild-type (WT) and blocks Lox-1–WT–induced cell signaling. Based on the use of molecular imaging techniques with laser scanning confocal microscopy and immunoprecipitation in an hLox-1–expressing Chinese hamster ovary cell system, homodimerization of hLox-1–WT was localized in the cell membrane, and Ox-LDL activated extracellular signal regulated kinase (ERK)1/2 without the translocation of hLox-1-WT. Lys <jats:sup>266</jats:sup> and Lys <jats:sup>267</jats:sup> of hLox-1, corresponding with Lys <jats:sup>262</jats:sup> and Lys <jats:sup>263</jats:sup> of bLox-1, were mutated (hLox1-K266A/K267A), and the mutant receptor inhibited hLox-1–WT–induced thymidine incorporation and ERK1/2 activation. Although Ox-LDL binds to the dominant-negative mutant receptor and is taken up by cytoplasm, ERK1/2 activation was blocked by heterodimerization with the mutant receptor and hLox-1–WT in the cell membrane. In addition, in human coronary artery smooth muscle cells, which express hLox-1–WT, we confirmed that the activation of ERK1/2 and [ <jats:sup>3</jats:sup> H]-thymidine incorporation was caused by the addition of Ox-LDL, and these actions were blocked by hLox1-K266A/K267A. In conclusion, the present findings constitute the first evidence that strategies aimed at blocking cell-proliferative pathways at the receptor level could be useful for impairing Lox-1–induced cell proliferation. </jats:p>

収録刊行物

  • Hypertension

    Hypertension 48 (2), 294-300, 2006-08

    Ovid Technologies (Wolters Kluwer Health)

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