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© The Rockefeller University Press, 0022-1007/1997/12/1975/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 12, December 15, 1997 1975-1983

Article

The E1B 19K/Bcl-2–binding Protein Nip3 is a Dimeric Mitochondrial Protein that Activates Apoptosis

Gao Chen*, Reena Ray*, Don Dubik*, Lianfa Shi*, Jeannick Cizeau, R. Chris Bleackley{ddagger}, Satya Saxena*, R. Dan Gietz§, and Arnold H. Greenberg*,§

From the * Manitoba Institute of Cell Biology and the § Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and the {ddagger} Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

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.

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: agreenb{at}cc.umanitoba.ca

1 Abbreviations used in this paper: {alpha}-MEM, {alpha}-minimal essential medium; 3AT, 3-amino-1,2,4-triazole.


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