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Volume 272, Number 6, Issue of February 7, 1997 pp. 3133-3136
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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COMMUNICATION:
Cyclic ADP-ribose Binds to FK506-binding Protein 12.6 to Release Ca²⁺ from Islet Microsomes^*

(Received for publication, November 11, 1996, and in revised form, December 6, 1996)

Naoya Noguchi , Shin Takasawa , Koji Nata , Akira Tohgo , Ichiro Kato , Fumiko Ikehata , Hideto Yonekura and Hiroshi Okamoto ^§

From the Department of Biochemistry, Tohoku University School of Medicine, Sendai 980-77, Miyagi, Japan

ABSTRACT

INTRODUCTION

EXPERIMENTAL PROCEDURES

RESULTS AND DISCUSSION

FOOTNOTES

Acknowledgments

REFERENCES

ABSTRACT

Cyclic ADP-ribose (cADPR) is a second messenger for Ca²⁺ mobilization via the ryanodine receptor (RyR) from islet microsomes for insulin secretion (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373). In the present study, FK506, an immunosuppressant that prolongs allograft survival, as well as cADPR were found to induce the release of Ca²⁺ from islet microsomes. After islet microsomes were treated with FK506, the Ca²⁺ release by cADPR from microsomes was reduced. cADPR as well as FK506 bound to FK506-binding protein 12.6 (FKBP12.6), which we also found occurs naturally in islet microsomes. When islet microsomes were treated with cADPR, FKBP12.6 dissociated from the microsomes and moved to the supernatant, releasing Ca²⁺ from the intracellular stores. The microsomes that were then devoid of FKBP12.6 did not show Ca²⁺ release by cADPR. These results strongly suggest that cADPR may be the ligand for FKBP12.6 in islet RyR and that the binding of cADPR to FKBP12.6 frees the RyR from FKBP12.6, causing it to release Ca²⁺.

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INTRODUCTION

Glucose is the primary stimulus of insulin secretion and synthesis in the pancreatic islets of Langerhans (1-3). Cyclic ADP-ribose (cADPR)¹ is generated in pancreatic islets by glucose stimulation, serving as a second messenger for Ca²⁺ mobilization in the endoplasmic reticulum to secrete insulin (4-6). cADPR activates the ryanodine receptor (RyR) of a variety of cells to release Ca²⁺ from the intracellular stores (4, 6-16). RyRs have been purified from both skeletal and cardiac muscle (17, 18), and FK506-binding protein 12 (FKBP12) and FK506-binding protein 12.6 (FKBP12.6) were copurified with type 1 RyR from striated muscle and with type 2 RyR from cardiac muscle, respectively (19, 20). FKBP12 and FKBP12.6 were shown to bind selectively to type 1 and type 2 RyR, respectively (21). It was reported that the type 1 RyR was activated by dissociation of FKBP12 from the RyR by the addition of FK506 to release Ca²⁺ (22).

In the present study, we show that cADPR binds to FKBP12.6, that FKBP12.6 is present in islet microsomes, and that when cADPR was added to islet microsomes, FKBP12.6 was dissociated from the microsomes to release Ca²⁺.

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EXPERIMENTAL PROCEDURES

Materials

Calmodulin was purchased from Calbiochem. Fluo 3 was obtained from Molecular Probes. 17-Allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0^4,9]octacos-18-ene-2,3,10,16-tetrone (FK506) was kindly provided by Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). A sheep anti-mouse antibody labeled with horseradish peroxidase and ECL reagents were from Amersham Corp., a goat anti-rabbit antibody labeled with horseradish peroxidase was from Zymed (San Francisco, CA), Immobilon-P was from Millipore (Bedford, MA), pMALc2 vector and amylose resin were from New England Biolabs (Beverly, MA), [proryl-³H]dihydro-FK506 and [³H]NAD⁺ were from DuPont NEN, NAD⁺ was from Boeringer, ATP and ADP-ribose were from Sigma, nicotinamide was from Wako Pure Chemical Industries, Ltd. (Osaka, Japan), and D-myo-inositol 1,4,5-trisphosphate and ryanodine were from Biomol Research (Natick, MA). A monoclonal antibody against human FKBP12 (clone 3F4-70) was kindly provided by Kazuyuki Otsuka and Dr. Masakazu Kobayashi ( Fujisawa Pharmaceutical Co., Ltd.), and an anti-FKBP12.6 antiserum, which also reacts with rat FKBP12, was kindly provided by Gou Ichien (Esai Co., Ltd., Tokyo).

Calcium Release Assay

Microsomes were prepared as described previously (4, 6). In brief, 2,000 islets from Wistar male rats (240-280 g) were homogenized with a Pellet mixer (Treff, Degersheim, Switzerland) in 0.2 ml of acetate intracellular medium composed of 250 mM potassium acetate, 250 mM N-methylglucamine, 1 mM MgCl₂, and 20 mM Hepes (pH 7.2) supplemented with 0.5 mM ATP, 4 mM phosphocreatine, creatine phosphokinase (2 units/ml), 2.5 mM benzamidine, and 0.5 mM phenylmethylsulfonyl fluoride. After the homogenates had been centrifuged for 45 s at 13,000 × g, the microsomes were prepared by Percoll density gradient centrifugation at 20,000 × g for 40 min at 10 °C. Release of Ca²⁺ was monitored in 0.6 ml of intracellular medium composed of 250 mM potassium gluconate, 250 mM N-methylglucamine, 1 mM MgCl₂, and 20 mM Hepes (pH 7.2) supplemented with 1 mM ATP, 4 mM phosphocreatine, creatine phosphokinase (2 units/ml), 2.5 mM benzamidine, 0.5 mM phenylmethylsulfonyl fluoride, 7 µg/ml bovine brain calmodulin (6), and 3 µM Fluo 3 with the addition of 30 µl of the islet microsome fraction (10 µg of protein) (4, 6). FK506 or cADPR (4, 6) was added into the incubation, and Fluo 3 fluorescence was measured at 490 nm excitation and 535 nm emission with a JASCO CAF-110 intracellular ion analyzer (Tokyo, Japan) at 37 °C (6). Total accumulated Ca²⁺ in islet microsomes was estimated by the increase of Fluo 3 fluorescence caused by the addition of 200 nM ionomycin (Sigma) to the Ca²⁺ release medium containing the microsomes, and the ambient free Ca²⁺ concentration ([Ca²⁺]) was calculated using the following equation, as described previously (6): [Ca²⁺] = K_d × (F  F_min)/(F_max  F), where K_d = 400 nM. In response to 100 nM cADPR, islet microsomes exhibited 18 ± 2 nmol Ca²⁺ release/mg protein, which corresponded to 31 ± 4% of the total accumulated Ca²⁺.

cDNA Cloning

1 µl of rat islet cDNA library (2 × 10⁶ plaque-forming unit) (23, 24) was used as a template for PCR (23-25). The sequences of sense and antisense primers were 5-GGAATTCCGCGTCCTTTTCCTCCTCCT-3 and 5-GGAATTCCTTGAGGTTTATGGCATATAGTT-3 for the isolation of rat FKBP12 cDNA, which corresponded to nucleotide sequences 48-68 and 636-658 of mouse FKBP12 mRNA (26), and 5-ATGGGCGTGGAGATCGAGA-3 and 5-CAAGCTTGGAAGGACATTCCCCAAGAA-3 for the isolation of rat FKBP12.6 cDNA, which corresponded to nucleotide sequences 1-19 and 306-326 of human FKBP12.6 mRNA (27, 28). Nucleotide sequences were determined as described (23, 25).

RT-PCR

RT-PCR was performed as described previously (23, 24). The oligonucleotides corresponding to 48-68 (5-CCCGAAGCGCGGCCAGACCTG-3) and 515-536 (5-TAGGTCAACACACATACAGAAG-3) of rat FKBP12 mRNA, 37-57 (5-GGAAGGACATTCCCTAAGAAG-3) and 237-257 (5-GTAGCTCCATATGCCACATCA-3) of rat FKBP12.6 mRNA, and 135-155 and 951-971 of rat glyceraldehyde-3-phosphate dehydrogenase mRNA (29) were used as PCR primers.

Immunoblot Analysis

Rat islet microsomes (100 µg of protein) were chromatographed on 20% SDS-polyacrylamide gel electrophoresis (30) and transferred to Immobilon P. The membrane was incubated with a monoclonal antibody against human FKBP12 or with an anti-FKBP12.6 antiserum, which also reacts with rat FKBP12 (see Fig. 4A). The monoclonal antibody was diluted at 0.2 µg/ml, and the antiserum was diluted 2000 times with 5% milk powder. After rinsing, the membrane was incubated with a sheep anti-mouse antibody labeled with horseradish peroxidase or with a goat anti-rabbit antibody labeled with horseradish peroxidase and developed using the ECL reagents as described (6, 25).

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Fig. 4. FKBP12.6 dissociation and Ca²⁺ release from islet microsomes by cADPR. A, dissociation of FKBP12.6 from islet microsomes by cADPR. Islet microsomes (100 µg of protein) were treated at 37 °C for 3 min with or without 1 µM cADPR in the Ca²⁺ release medium described under "Experimental Procedures" and centrifuged at 100,000 × g for 60 min at 4 °C, and the resultant pellet and supernatant were analyzed by immunoblot using an anti-FKBP12.6 antibody. Lane 1, 50 ng of FKBP12.6; lane 2, 20 ng of FKBP12.6; lane 3, 10 ng of FKBP12.6; lane 4, supernatant derived from islet microsomes treated without cADPR; lane 5, pellet derived from islet microsomes treated without cADPR; lane 6, supernatant derived from cADPR-treated islet microsomes; lane 7, pellet derived from cADPR-treated islet microsomes; lane 8, 20 ng of FKBP12. The arrow indicates the position of FKBP12.6. B, Ca²⁺ release by cADPR and FK506 from islet microsomes after the cADPR pretreatment. Islet microsomes (10 µg of protein) were treated at 37 °C for 3 min with the indicated concentrations of cADPR in the Ca²⁺ release medium and centrifuged at 100,000 × g for 60 min at 4 °C. The resultant pellet was resuspended in 0.6 ml of the Ca²⁺ release medium, and Ca²⁺ release was induced by the addition of 100 nM cADPR () or 10 µM FK506 () and measured as described under "Experimental Procedures."
[View Larger Version of this Image (14K GIF file)]

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cADPR Binding Assay

The cDNA encoding rat FKBP12.6 was subcloned into a pMALc2 vector and recombinant maltose binding protein (MBP)-FKBP12.6 fusion protein was expressed in the cytoplasm of Escherichia coli. The fusion protein was purified to homogeneity by amylose resin chromatography. MBP-FKBP12.6 fusion protein (100 nM) was incubated with the indicated concentrations of FK506 or cADPR in the presence of [proryl-³H]dihydro-FK506 (0.5 µCi) or [³H]cADPR (0.5 µCi) that was prepared from [³H]NAD⁺ by Aplysia kurodai ADP-ribosyl cyclase (4, 6) in Dulbecco's phosphate-buffered saline at 25 °C for 30 min. MBP-FKBP12.6 was precipitated with amylose resin, and the radioactivity of the precipitate was measured with a Beckman scintillation spectrometer (LS-6500). K_d values were calculated using DeltaGraph® Pro 3 (DeltaPoint, Inc.). The binding specificity of FKBP12.6 was examined as described above using 100 nM of [proryl-³H]dihydro-FK506 or [³H]cADPR with 100 µM of cADPR, FK506, NAD⁺, ATP, ADP-ribose, nicotinamide, D-myo-inositol 1,4,5-trisphosphate, and ryanodine as competitors.

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RESULTS AND DISCUSSION

We have previously shown that islet microsomes release Ca²⁺ in response to cADPR (4). In the present study, we found that FK506, one of the most widely used immunosuppressive agents, induced the release of Ca²⁺ from islet microsomes. The dose-response curve of FK506 on the Ca²⁺ release from islet microsomes was concentration-dependent, with half-maximal release occurring at 2 µM, and maximal Ca²⁺ release occurring at 10 µM (Fig. 1A). In addition, as shown in Fig. 1B, after the islet microsomes were treated with FK506, the Ca²⁺ release by cADPR from the microsomes was reduced depending on the concentration of FK506; the maximal reduction was seen at 5-25 µM FK506. Because cADPR and FK506 appear to induce the release of Ca²⁺ by a common mediator, we next tried to determine if this occurs by a targeting of the same ligand. The cellular target for FK506 is thought to be FKBP12 and FKBP12.6. Therefore, we isolated FKBP12 and FKBP12.6 cDNAs from a rat islet cDNA library. As shown in Fig. 2A, rat FKBP12 is composed of 108 amino acids and highly conserved with human (31, 32), mouse (26), bovine (33), and rabbit (19) FKBP12. Rat FKBP12.6 is also a 108-amino acid protein and completely conserved with human (27, 28) and bovine (33) FKBP12.6. RT-PCR analyses revealed that FKBP12 and FKBP12.6 mRNAs were ubiquitously expressed in rat tissues including pancreatic islets and streptozotocin/nicotinamide-induced insulinomas (Fig. 2B); FKBP12 mRNA was detected in RINm5F cells, but FKBP12.6 mRNA was not. RINm5F cells, rat insulinoma-derived immortal cells, which do not release Ca²⁺ in response to cADPR (34), synthesize and secrete very little insulin and show negligible sensitivity to glucose (35). Streptozotocin/nicotinamide-induced insulinomas contain as much insulin mRNA as normal islets (36-38) and retain the sensitivity to glucose (39). Therefore, it is FKBP12.6 rather than FKBP12 that plays a role in the CD38-cADPR signaling (5) in insulin secretion by glucose in islets, because CD38, which catalyzes the synthesis and degradation of cADPR (23, 40, 41), a second messenger for Ca²⁺ mobilization in glucose-induced insulin secretion in islets (4, 5), is expressed in islets and streptozotocin/nicotinamide-induced insulinomas but not in RINm5F cells (23, 24). We then isolated microsomes from rat islets and carried out immunoblot analyses. As shown in Fig. 2 (C and D), although islet microsomes did not contain FKBP12 (Fig. 2C, lane 4), the microsomes contained FKBP12.6 (Fig. 2D, lanes 5 and 6), suggesting that FKBP12.6 is the target for FK506 and/or cADPR to release Ca²⁺ from islet microsomes.

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Fig. 1. Effects of FK506 on Ca²⁺ release from islet microsomes. A, Ca²⁺ release by FK506 from islet microsomes. Ca²⁺ release was induced by FK506 at the indicated concentrations. The Ca²⁺ release measurement was a peak value estimated from Fluo 3 fluorescence (6). B, Ca²⁺ release by cADPR from islet microsomes after the FK506-induced Ca²⁺ release. Islet microsomes were incubated in 0.6 ml of Ca²⁺ release medium for 10 min with the indicated concentrations of FK506 and then challenged with the addition of 3 µl of 20.1 µM cADPR to the medium (the final cADPR concentration was 100 nM).
[View Larger Version of this Image (16K GIF file)]

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Fig. 2. Amino acid sequence of rat FKBP12/12.6, the mRNA expression in rat tissues and existence of FKBP12.6 in islet microsomes. A, deduced amino acid sequence of rat FKBP12 and alignment with human (31, 32), mouse (26), bovine (33), and rabbit (19) FKBP12 and rat, human (27, 28), and bovine (33) FKBP12.6. Identical residues are indicated by dots. B, RT-PCR detection of rat FKBP12 and FKBP12.6 mRNAs. Lane 1, liver; lane 2, spleen; lane 3, thymus; lane 4, alveolar macrophage; lane 5, islets; lane 6, streptozotocin/nicotinamide-induced insulinomas; lane 7, RINm5F cells; lane 8, cerebellum; lane 9, cerebrum; lane 10, heart; lane 11, salivary gland; lane 12, skeletal muscle; lane 13, kidney. C, immunoblot analysis of FKBP12. Lane 1, 50 ng of FKBP12; lane 2, 20 ng of FKBP12; lane 3, 50 ng of FKBP12.6; lane 4, islet microsomes (100 µg of protein); lane 5, cerebellar microsomes (100 µg of protein). D, immunoblot analysis of FKBP12.6 in islet microsomes. Lane 1, 50 ng of FKBP12.6; lane 2, 20 ng of FKBP12.6; lane 3, 10 ng of FKBP12.6; lane 4, 10 ng of FKBP12; lane 5, islet microsomes (100 µg of protein); lane 6, islet microsomes (50 µg of protein). G3PDH, glyceraldehyde-3-phosphate dehydrogenase.
[View Larger Version of this Image (28K GIF file)]

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Next, we examined the binding of FKBP12.6 to cADPR. The recombinant rat FKBP12.6 bound to FK506 at a K_d value of 32 nM. As shown in Fig. 3A, cADPR was found to bind to FKBP12.6 at a K_d value of 35 nM. The cADPR binding was inhibited by FK506 and neither structurally nor functionally related analogues of cADPR inhibited the cADPR binding to FKBP12.6 (Fig. 3B). These results indicate that FKBP12.6 acts as a cADPR-binding protein and strongly suggest that cADPR is the actual ligand for FKBP12.6 because FK506 does not normally exist in mammalian cells.

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Fig. 3. cADPR binding activity of FKBP12.6. A, binding of cADPR to recombinant FKBP12.6. 90% of the total binding was displaced by cold cADPR as plotted in B. B, effect of structural or functional analogues of cADPR on cADPR binding of FKBP12.6. The bar graph represents the means ± S.E. of n = 3-5 measurements. The results of two-tailed Student's t test comparing the binding to each addition versus the control without competitor are shown. ADPR, ADP-ribose; NA, nicotinamide.
[View Larger Version of this Image (28K GIF file)]

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It was reported that FKBP12/12.6 bound to RyR tightly and that by the addition of FK506, FKBP12/12.6 were dissociated from RyR to form FK506-FKBP12/12.6 complexes (19, 22, 33). In addition, the open probability of the type 1 RyR Ca²⁺ channel was greatly increased when FKBP12 was released from the RyR by the addition of FK506 (22). As shown in Fig. 4, after treatment of islet microsomes with cADPR, FKBP12.6 was not detected in the microsomes but was recovered in the supernatant (Fig. 4A), and Ca²⁺ release from the microsome treated by cADPR or FK506 was reduced. FK506 as well as cADPR then had almost no effect in releasing Ca²⁺ from the 1 µM cADPR-pretreated microsomes (Fig. 4B). Our recent experiment indicated that type 2 RyR is expressed in rat islets.² From these results, it is strongly suggested that when cADPR binds to FKBP12.6 in islet microsome RyR and causes the dissociation of FKBP12.6 from the RyR to form FKBP12.6-cADPR complex, the channel activity of the RyR is thereby increased to release Ca²⁺ from the endoplasmic reticulum. As described previously (6), the RyR can also be activated by Ca²⁺/calmodulin-dependent protein kinase II. The interaction between the dissociation of FKBP12.6 from RyR and the phosphorylation of RyR by Ca²⁺/calmodulin-dependent protein kinase II remains to be elucidated.

FOOTNOTES

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) D86641[GenBank] and D86642[GenBank].

Acknowledgments

We are grateful to Kazuyuki Otsuka and Masakazu Kobayashi (Fujisawa Pharmaceutical Co., Ltd.) for providing the antibody against FKBP12, Gou Ichien (Esai Co., Ltd., Tokyo) for providing the antiserum against FKBP12.6, Hideo Kumagai for technical assistance, and Brent Bell for valuable assistance in preparing the manuscript for publication.

REFERENCES

1. Hedeskov, C. J. (1980) Physiol. Rev. 60, 442-509 [Free Full Text]
2. Itoh, N., and Okamoto, H. (1980) Nature 283, 100-102 [CrossRef][Medline] [Order article via Infotrieve]
3. Okamoto, H. (1981) Mol. Cell. Biochem. 37, 43-61 [CrossRef][Medline] [Order article via Infotrieve]
4. Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373 [Abstract/Free Full Text]
5. Okamoto, H., Takasawa, S., and Tohgo, A. (1995) Biochimie 77, 356-363 [Medline] [Order article via Infotrieve]
6. Takasawa, S., Ishida, A., Nata, K., Nakagawa, K., Noguchi, N., Tohgo, A., Kato, I., Yonekura, H., Fujisawa, H., and Okamoto, H. (1995) J. Biol. Chem. 270, 30257-30259 [Abstract/Free Full Text]
7. Galione, A., Lee, H. C., and Busa, W. B. (1991) Science 253, 1143-1146 [Abstract/Free Full Text]
8. Koshiyama, H., Lee, H. C., and Tashjian, A. H., Jr. (1991) J. Biol. Chem. 266, 16985-16988 [Abstract/Free Full Text]
9. Mészáros, L. G., Bak, J., and Chu, A. (1993) Nature 364, 76-79 [CrossRef][Medline] [Order article via Infotrieve]
10. Hua, S.-Y., Tokimasa, T., Takasawa, S., Furuya, Y., Nohmi, M., Okamoto, H., and Kuba, K. (1994) Neuron 12, 1073-1079 [CrossRef][Medline] [Order article via Infotrieve]
11. Thorn, P., Gerasimenko, O., and Petersen, O. H. (1994) EMBO J. 13, 2038-2043 [Medline] [Order article via Infotrieve]
12. Kuemmerle, J. F., and Makhlouf, G. M. (1995) J. Biol. Chem. 270, 25488-25494 [Abstract/Free Full Text]
13. Gromada, J., Jørgensen, T. D., and Dissing, S. (1995) FEBS Lett. 360, 303-306 [CrossRef][Medline] [Order article via Infotrieve]
14. Sitsapesan, R., and Williams, A. J. (1995) Am. J. Physiol. 268, C1235-C1240 [Abstract/Free Full Text]
15. Rakovic, S., Galione, A., Ashamu, G. A., Potter, B. V. L., and Terrar, D. A. (1996) Curr. Biol. 6, 989-996 [CrossRef][Medline] [Order article via Infotrieve]
16. Clementi, E., Riccio, M., Sciorati, C., Nisticò, G., and Meldolesi, J. (1996) J. Biol. Chem. 271, 17739-17745 [Abstract/Free Full Text]
17. Inui, M., Saito, A., and Fleischer, S. (1987) J. Biol. Chem. 262, 1740-1747 [Abstract/Free Full Text]
18. Inui, M., Saito, A., and Fleischer, S. (1987) J. Biol. Chem. 262, 15637-15642 [Abstract/Free Full Text]
19. Jayaraman, T., Brillantes, A.-M., Timerman, A. P., Fleischer, S., Erdjument-Bromage, H., Tempst, P., and Marks, A. R. (1992) J. Biol. Chem. 267, 9474-9477 [Abstract/Free Full Text]
20. Timerman, A. P., Jayaraman, T., Wiederrecht, G., Onoue, H., Marks, A. R., and Fleischer, S. (1994) Biochem. Biophys. Res. Commun. 198, 701-706 [CrossRef][Medline] [Order article via Infotrieve]
21. Timerman, A. P., Onoue, H., Xin, H.-B., Barg, S., Copello, J., Wiederrecht, G., and Fleischer, S. (1996) J. Biol. Chem. 271, 20385-20391 [Abstract/Free Full Text]
22. Brillantes, A.-M., Ondrias, K., Scott, A., Kobrinsky, E., Ondriasov, E., Moschella, M. C., Jayaraman, T., Landers, M., Ehrlich, B. E., and Marks, A. (1994) Cell 77, 513-523 [CrossRef][Medline] [Order article via Infotrieve]
23. Koguma, T., Takasawa, S., Tohgo, A., Karasawa, T., Furuya, Y., Yonekura, H., and Okamoto, H. (1994) Biochim. Biophys. Acta 1223, 160-162 [Medline] [Order article via Infotrieve]
24. Furuya, Y., Takasawa, S., Yonekura, H., Tanaka, T., Takahara, J., and Okamoto, H. (1995) Gene (Amst.) 165, 329-330 [CrossRef][Medline] [Order article via Infotrieve]
25. Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H. (1993) J. Biol. Chem. 268, 26052-26054 [Abstract/Free Full Text]
26. Nelson, P. A., Lippke, J. A., Murcko, M. A., Rosborough, S. L., and Peattie, D. A. (1991) Gene (Amst.) 109, 255-258 [CrossRef][Medline] [Order article via Infotrieve]
27. Arakawa, H., Nagase, H., Hayashi, N., Fujiwara, T., Ogawa, M., Shin, S., and Nakamura, Y. (1994) Biochem. Biophys. Res. Commun. 200, 836-843 [CrossRef][Medline] [Order article via Infotrieve]
28. Lam, E., Martin, M. M., Timerman, A. P., Sabers, C., Fleischer, S., Lukas, T., Abraham, R. T., O'Keefe, S. J., O'Neill, E. A., and Wiederrecht, G. J. (1995) J. Biol. Chem. 270, 26511-26522 [Abstract/Free Full Text]
29. Tso, J. Y., Sun, X. H., Kao, T. H., Reece, K. S., and Wu, R. (1985) Nucleic Acids Res. 13, 2485-2502 [Abstract/Free Full Text]
30. Okajima, T., Tanabe, T., and Yasuda, T. (1993) Anal. Biochem. 211, 293-300 [CrossRef][Medline] [Order article via Infotrieve]
31. Maki, N., Sekiguchi, F., Nishimaki, J., Miwa, K., Hayano, T., Takahashi, N., and Suzuki, M. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 5440-5443 [Abstract/Free Full Text]
32. Standaert, R. F., Galat, A., Verdine, G. L., and Schreiber, S. L. (1990) Nature 346, 671-674 [CrossRef][Medline] [Order article via Infotrieve]
33. Sewell, T. J., Lam, E., Martin, M. M., Leszyk, J., Weidner, J., Calaycay, J., Griffin, P., Williams, H., Hung, S., Cryan, J., Sigal, N. H., and Wiederrecht, G. J. (1994) J. Biol. Chem. 269, 21094-21102 [Abstract/Free Full Text]
34. Islam, Md. S., Larsson, O., Berggren, P.-O., Takasawa, S., Nata, K., Yonekura, H., Okamoto, H., and Galione, A. (1993) Science 262, 584-586 [Free Full Text]
35. Praz, G. A., Halban, P. A., Wollheim, C. B., Blondel, B., Strauss, A. J., and Renold, A. E. (1983) Biochem. J. 210, 345-352 [Medline] [Order article via Infotrieve]
36. Itoh, N., and Okamoto, H. (1977) FEBS Lett. 80, 111-114 [CrossRef][Medline] [Order article via Infotrieve]
37. Itoh, N., Nose, K., and Okamoto, H. (1979) Eur. J. Biochem. 97, 1-9 [CrossRef][Medline] [Order article via Infotrieve]
38. Yamagami, T., Miwa, A., Takasawa, S., Yamamoto, H., and Okamoto, H. (1985) Cancer Res. 45, 1845-1849 [Abstract/Free Full Text]
39. Masiello, P., Wollheim, C. B., Cori, Z., Blondel, B., and Bergamini, E. (1984) Toxicol. Pharmacol. 12, 274-280
40. Tohgo, A., Takasawa, S., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Furuya, Y., Yonekura, H., and Okamoto, H. (1994) J. Biol. Chem. 269, 28555-28557 [Abstract/Free Full Text]
41. Kato, I., Takasawa, S., Akabane, A., Tanaka, O., Abe, H., Takamura, T., Suzuki, Y., Nata, K., Yonekura, H., Yoshimoto, T., and Okamoto, H. (1995) J. Biol. Chem. 270, 30045-30050 [Abstract/Free Full Text]

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