Nip3 (nineteen kD interacting protein-3) is an E1B 19K and Bcl-2 binding protein of unknown function. Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. Nip3 is expressed in mitochondria and a mutant (Nip3163) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. Transient transfection of epitope-tagged Nip3 in Rat-1 fibroblasts and MCF-7 breast carcinoma induces apoptosis within 12 h while cells transfected with the Nip3163 mutant have a normal phenotype, suggesting that mitochondrial localization is necessary for induction of cell death. Nip3 overexpression increases the sensitivity to apoptosis induced by granzyme B and topoisomerase I and II inhibitors. After transfection, both Nip3 and Nip3163 protein levels decrease steadily over 48 h indicating that the protein is rapidly degraded and this occurs in the absence of cell death. Bcl-2 overexpression initially delays the onset of apoptosis induced by Nip3 but the resistance is completely overcome in longer periods of incubation. Nip3 protein levels are much higher and persist longer in Bcl-2 expressing cells. In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression.
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15 December 1997
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December 15 1997
The E1B 19K/Bcl-2–binding Protein Nip3 is a Dimeric Mitochondrial Protein that Activates Apoptosis
Gao Chen,
Gao Chen
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Reena Ray,
Reena Ray
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Don Dubik,
Don Dubik
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Lianfa Shi,
Lianfa Shi
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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R. Chris Bleackley,
R. Chris Bleackley
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Satya Saxena,
Satya Saxena
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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R. Dan Gietz,
R. Dan Gietz
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Arnold H. Greenberg
Arnold H. Greenberg
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
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Gao Chen
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Reena Ray
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Don Dubik
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Lianfa Shi
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Jeannick Cizeau
R. Chris Bleackley
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Satya Saxena
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
R. Dan Gietz
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Arnold H. Greenberg
From the *Manitoba Institute of Cell Biology and the §Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the ‡Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
Address correspondence to Arnold H. Greenberg, Manitoba Institute of Cell Biology, University of Manitoba, 100 Olivia St., Winnipeg, MB Canada R3E OV9. Phone (204) 787-2112; Fax: (204) 787-2190; E-mail: [email protected]
1
Abbreviations used in this paper: α-MEM, α-minimal essential medium; 3AT, 3-amino-1,2,4-triazole.
Received:
May 15 1997
Revision Received:
September 03 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (12): 1975–1983.
Article history
Received:
May 15 1997
Revision Received:
September 03 1997
Citation
Gao Chen, Reena Ray, Don Dubik, Lianfa Shi, Jeannick Cizeau, R. Chris Bleackley, Satya Saxena, R. Dan Gietz, Arnold H. Greenberg; The E1B 19K/Bcl-2–binding Protein Nip3 is a Dimeric Mitochondrial Protein that Activates Apoptosis . J Exp Med 15 December 1997; 186 (12): 1975–1983. doi: https://doi.org/10.1084/jem.186.12.1975
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