| Co-Investigator(Kenkyū-buntansha) |
KUROKAWA Mineo University of Tokyo Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助手 (80312320)
OGAWA Seishi University of Tokyo Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助手 (60292900)
CHIBA Shigeru University of Tokyo Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助手 (60212049)
TAKAHASHI Tsuyoshi University of Tokyo Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助手
TAKAHASHI Tokiharu University of Tokyo Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助手 (30313125)
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| Research Abstract |
p130cas is a docking protein that contains an SH3 domain and multiple tyrosine residues. p130cas is located at focal adhesions, is tyrosine phosphorylated in response to integrin stimulation, and is thought to transmit signals, via c-Crk and other proteins, to the remodeling of actin stress fibers and to the cell movement. In the search for the ligands of the SH3 domain of p130cas by Far Western screening, we cloned a novel protein named CIZ.CIZ consists of a putative leucine zipper, serine/threonine rich region, a proline rich sequence, 5, 6 or 8 Kruppel-type C2H2 zinc fingers, and the glutamine-alanine repeat. CIZ binds Cas in cells and is located in nucleus and at focal adhesions. We showed that CIZ is a nucleo-cytoplasmic shuttling protein, using the transient interspecies heterokaryon formation assay. In order to search for the targets of CIZ in nucleus, we determined the DNA binding consensus of CIZ as (G/C)AAAAA(A) by CASTing analysis. The consensus-like sequences are found in several promoters of matrix metalloproteinases, which are the enzymes to degrade the extracellular matrix proteins. CIZ binds to a consensus-like sequence in MMP-1 (collagenase) promoter. Overexpression of CIZ upregulates the transcriptions from MMP-1, MMP-3 (stromelysin), and MMP-7 (matrilysin) promoters, and this transactivation was enhanced in the presense of Cas. Furthermore, the stable overexpression of CIZ promoted the production of MMP-7 in culture medium. In summary, CIZ, a novel zinc finger protein, binds Cas, is a nucleo-cytoplasmic shuttling protein, and regulates the expression of matrix metalloproteinases.
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