Regulation of tumor necrosis factor-and Fas-mediated apoptotic cell death by a novel cDNA TR2L.
A novel cDNA, TR2L, isolated from murine NIH 3T3 fibroblasts, was found to modulate tumor necrosis factor (TNF)-mediated apoptosis in murine L929 fibrosarcoma cells. The full-length cDNA (853 bp) encodes a predicted coding region of 56 amino acids (6.3 kD), with 53.6% identity to the C-terminus of rat transcriptional activator FE65. When expressed stably in L929 cells, TR2L protein inhibited TNF cytotoxic response. In contrast, TR2L enhanced anti-Fas antibodies/actinomycin D (ActD)-mediated L929 apoptosis. Alteration of TR2L function occurred by tagging this protein with a 6xHis fragment to the N-terminus (designated 6xH-TR2L). L929 cells which stably expressed 6xH-TR2L acquired a significantly enhanced TNF apoptotic response and increased genomic DNA fragmentation compared to control cells. Enhanced cell death also occurred in these 6xH-TR2L-expressing cells under serum starvation conditions. In contrast, the anti-Fas/ActD-mediated apoptosis was blocked by the 6xH-TR2L protein. Functional role of TR2L protein in regulation of cancer cell susceptibility to TNF-and Fas ligand-mediated apoptosis is suggested.
Cao
H
H
Guthrie Research Institute, Laboratory of Molecular Immunology Guthrie Medical Center, Sayre, Pennsylvania 18840, USA.
Mattison
J
J
Zhao
Y
Y
Joki
N
N
Grasso
M
M
Chang
N S
NS
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D001483:Base Sequence; D002352:Carrier Proteins; D018076:DNA, Complementary; D051379:Mice; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C101886:Apbb2 protein, mouse; D002352:Carrier Proteins; D018076:DNA, Complementary; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor