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Molecular and Cellular Biology, April 1999, p. 3145-3155, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

SAG, a Novel Zinc RING Finger Protein That Protects Cells from Apoptosis Induced by Redox Agents

Hangjun Duan,1 Yuli Wang,1 Micheal Aviram,2,dagger Manju Swaroop,1 Joseph A. Loo,3 Junhui Bian,1,Dagger Ye Tian,1 Tom Mueller,1 Charles L. Bisgaier,2,§ and Yi Sun1,*

Departments of Molecular Biology,1 Cardiac and Vascular Diseases,2 and Chemistry,3 Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105

Received 18 November 1998/Returned for modification 22 December 1998/Accepted 11 January 1999

SAG (sensitive to apoptosis gene) was cloned as an inducible gene by 1,10-phenanthroline (OP), a redox-sensitive compound and an apoptosis inducer. SAG encodes a novel zinc RING finger protein that consists of 113 amino acids with a calculated molecular mass of 12.6 kDa. SAG is highly conserved during evolution, with identities of 70% between human and Caenorhabditis elegans sequences and 55% between human and yeast sequences. In human tissues, SAG is ubiquitously expressed at high levels in skeletal muscles, heart, and testis. SAG is localized in both the cytoplasm and the nucleus of cells, and its gene was mapped to chromosome 3q22-24. Bacterially expressed and purified human SAG binds to zinc and copper metal ions and prevents lipid peroxidation induced by copper or a free radical generator. When overexpressed in several human cell lines, SAG protects cells from apoptosis induced by redox agents (the metal chelator OP and zinc or copper metal ions). Mechanistically, SAG appears to inhibit and/or delay metal ion-induced cytochrome c release and caspase activation. Thus, SAG is a cellular protective molecule that appears to act as an antioxidant to inhibit apoptosis induced by metal ions and reactive oxygen species.

* Corresponding author. Mailing address: Department of Molecular Biology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105. Phone: (734) 622-1959. Fax: (734) 622-7158. E-mail: yi.sun{at}wl.com.

dagger Present address: Lipid Research Laboratory, Rambam Medical Center, Bat-Galim, Haifa 31096, Israel.

Dagger Present address: Abilene Christian University, Abilene, TX 79699.

§ Present address: Esperion Therapeutic, Inc., Ann Arbor, MI 48108.

Molecular and Cellular Biology, April 1999, p. 3145-3155, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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