Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine Family

doi:10.1074/jbc.271.22.12687

Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine Family*

From the Departments of ^‡ Molecular Oncology
^¶ Molecular Biology
^∥ Immunology, and
^″ Cell Biology, Genentech, Inc., South San Francisco, California 94080-4990

^‴ To whom correspondence should be addressed:
Dept. of Molecular Oncology, Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, CA 94080-4990.
Tel.: 415-225-1853; Fax: 415-225-6443; E-mail: aa{at}gene.com

Abstract

Cytokines in the tumor necrosis factor (TNF) family regulate development and function of the immune system. We have isolated a new member of this family, designated Apo-2 ligand (Apo-2L), via an expressed sequence tag. Apo-2L is a 281-amino acid protein, related most closely to Fas/Apo-1 ligand. Transfected Apo-2L is expressed at the cell surface with its C terminus exposed, indicating a type II transmembrane protein topology. Like Fas/Apo-1 ligand and TNF, the C-terminal extracellular region of Apo-2L (amino acids 114-281) exhibits a homotrimeric subunit structure. Soluble Apo-2L induces extensive apoptosis in lymphoid as well as non-lymphoid tumor cell lines. The effect of Apo-2L is not inhibited by soluble Fas/Apo-1 and TNF receptors; moreover, expression of human Fas/Apo-1 in mouse fibroblasts, which confers sensitivity to induction of apoptosis by agonistic anti-Fas/Apo-1 antibody, does not confer sensitivity to Apo-2L. Hence, Apo-2L acts via a receptor which is distinct from Fas/Apo-1 and TNF receptors. These results suggest that, along with other family members such as Fas/Apo-1 ligand and TNF, Apo-2L may serve as an extracellular signal that triggers programmed cell death.

Footnotes

↵§ The first two authors contributed equally to this work.
↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TNF

tumor necrosis factor

TNFR

tumor necrosis factor receptor

EST

expressed sequenced tag

mAb

monoclonal antibody

PI

propidium iodide

LT

lymphotoxin

FACS

fluorescence-activated cell sorter.
- Received March 12, 1996.