A nonsecretable cell surface mutant of tumor necrosis factor (TNF) kills by cell-to-cell contact.
In addition to the induction of tumor regression, tumor necrosis factor (TNF) has been implicated as the causative agent in a number of pathologies, including cachexia, septic shock, rheumatoid arthritis, autoimmunity, and induction of HIV expression. We propose that this complex physiology might be manifest by different forms of TNF: the 17 kd secretory component, the 26 kd transmembrane form, or both. To determine whether the 26 kd form of TNF was biologically active and whether its biology differed from that of the secretory component, we generated uncleavable and solely secretable mutants of TNF and studied their biological activities. We found that an uncleavable mutant of the 26 kd cell surface transmembrane form of TNF kills tumor cells and virus-infected cells by cell-to-cell contact, and that TNF need not be internalized by its target to kill. Thus, the 26 kd integral transmembrane form of TNF may function in vivo to kill tumor cells and other targets locally in contrast to the systemic bioactivity of the secretory component.
Department of Molecular Biology, Cetus Corporation, Emeryville, California 94608.
C
C
Perez
I
I
Albert
K
K
DeFay
N
N
Zachariades
L
L
Gooding
M
M
Kriegler
D000595:Amino Acid Sequence; D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002472:Cell Transformation, Viral; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D015345:Oligonucleotide Probes; D010641:Phenotype; D010957:Plasmids; D011994:Recombinant Proteins / Q000494:pharmacology; D015183:Restriction Mapping; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000494:pharmacology
D015345:Oligonucleotide Probes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha