TID1, a human homolog of the Drosophila tumor suppressor l(2)tid, encodes two mitochondrial modulators of apoptosis with opposing functions

Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8499-504. doi: 10.1073/pnas.96.15.8499.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Apoptosis / genetics*
  • Caspases / metabolism
  • Cloning, Molecular
  • Cytochrome c Group / metabolism
  • Drosophila / genetics*
  • Drosophila Proteins*
  • Genes, Tumor Suppressor / genetics*
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / genetics*
  • Humans
  • Microscopy, Fluorescence
  • Mitochondria / chemistry*
  • Mitochondrial Proteins
  • Mitomycin / pharmacology
  • Molecular Sequence Data
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • CG5504 protein, Drosophila
  • Cytochrome c Group
  • DNAJA3 protein, human
  • Drosophila Proteins
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Mitochondrial Proteins
  • Tumor Necrosis Factor-alpha
  • Mitomycin
  • Caspases