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.
Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, Boston, MA 02115, USA.
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De-Medina
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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