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Articles by T Kageyama
Total Records ( 2 ) for T Kageyama
  S Yuasa , T Onizuka , K Shimoji , Y Ohno , T Kageyama , S. H Yoon , T Egashira , T Seki , H Hashimoto , T Nishiyama , R Kaneda , M Murata , F Hattori , S Makino , M Sano , S Ogawa , O. W. J Prall , R. P Harvey and K. Fukuda

Rationale: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors.

Objective: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor.

Methods and Results: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or MHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls.

Conclusions: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network.

  R.M.C Deshapriya , S Yuhashi , M Usui , T Kageyama and Y. Yamamoto

To identify functionally essential sequences and residues of CTLA-2, in vitro mutagenesis was carried out. The coefficient of inhibition (Ki) was determined towards rabbit cathepsin L using Z-Phe-Arg-MCA as the substrate. Recombinant CTLA-2 inhibited the enzyme potently (Ki = 15 nM). A truncated mutant, lacking the N- and C-terminal Ala1–Asp9 and Leu80–Glu109 regions, was also a potent inhibitor (Ki = 10 nM). Subsequent short deletions in the central region (Asn10–Ser79) showed three functionally essential distinct regions: Asn10–Phe19, His30–Ala44 and Ser55–Ser79. These regions cover sequences corresponding to three helices (1, 2 and 3) and sequences that interact with the cognate enzyme. Alanine scanning showed that replacement of one of three conserved Trp residues increased the Ki by 15–20-fold; whereas, replacement of two/three Trp residues at once caused complete loss of potency, as did replacing Cys75 with Ala or Ser. The proteins from wild-type (WT) CTLA-2 and mutant C75A were stable overnight when incubated with cathepsin L; whereas, proteins from mutants W12A, W15A and W35A were quickly digested. Incubation of cathepsin L/WT CTLA-2 formed a complex; whereas, C75S did not form a complex. Our overall results point to a critical role of W12, W15, W35 and Cys75 residues in CTLA-2.

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