TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions.
Mitochondria have emerged as central regulators of apoptosis. Here, we show that TID1, a human homolog of the Drosophila tumor suppressor lethal (2) tumorous imaginal discs, l(2)tid, encodes two mitochondrial matrix proteins, designated hTid-1(L) and hTid-1(S). These splice variants are both highly conserved members of the DnaJ family of proteins, which regulate the activity of and confer substrate specificity to Hsp70 proteins. Both hTid-1(L) and hTid-1(S) coimmunoprecipitate with mitochondrial Hsp70. Expression of hTid-1(L) or hTid-1(S) have no apparent capacity to induce apoptosis but have opposing effects on apoptosis induced by exogenous stimuli. Expression of hTid-1(L) increases apoptosis induced by both the DNA-damaging agent mitomycin c and tumor necrosis factor alpha. This activity is J domain-dependent, because a J domain mutant of hTid-1(L) can dominantly suppress apoptosis. In sharp contrast, expression of hTid-1(S) suppresses apoptosis, whereas expression of a J domain mutant of hTid-1(S) increases apoptosis. Hence, we propose that TID1 gene products act to positively and negatively modulate apoptotic signal transduction or effector structures within the mitochondrial matrix.
Syken
J
J
Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, Boston, MA 02115, USA.
De-Medina
T
T
Münger
K
K
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D003001:Cloning, Molecular; D003574:Cytochrome c Group / Q000378:metabolism; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000737:chemistry*; D024101:Mitochondrial Proteins; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C093721:CG5504 protein, Drosophila; D003574:Cytochrome c Group; C120664:DNAJA3 protein, human; D029721:Drosophila Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D014409:Tumor Necrosis Factor-alpha; D016685:Mitomycin; D020169:Caspases