Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis factor-alpha-mediated death signaling.
Deleted in breast cancer-1 (DBC-1) was initially cloned from a homozygously deleted region in breast and other cancers on human chromosome 8p21, although no function is known for the protein product it encodes. We identified the generation of amino-terminally truncated versions of DBC-1 during tumor necrosis factor (TNF)-alpha-mediated apoptosis. Full-length 150 kDa DBC-1 underwent caspase-dependent processing during TNF-alpha-mediated death signaling, to produce p120 DBC-1 and p66 DBC-1 carboxy-terminal fragments. Endogenous DBC-1 localized to the nucleus in healthy cells, but localized to the cytoplasm during TNF-alpha-mediated apoptosis, consistent with the loss of the amino-terminus containing the nuclear localization signal. Overexpression of an amino-terminal truncated DBC-1, resembling p120 DBC-1, caused mitochondrial clustering, mitochondrial matrix condensation, and sensitized cells to TNF-alpha-mediated apoptosis. The carboxy-terminal coiled-coil domain of DBC-1 was responsible for the cytoplasmic and mitochondrial localization, and for the death-promoting activity of DBC-1. Thus, caspase-dependent processing of DBC-1 may act as a feed-forward mechanism to promote apoptosis and possibly also tumor suppression. DBC-1, like its homolog cell cycle and apoptosis regulatory protein-1 (CARP-1), may function in the regulation of apoptosis.
Sundararajan
Ramya
R
Rutgers University, 679 Hoes Lane, Room 140, Piscataway, NJ 08854, USA.
Chen
Guanghua
G
Mukherjee
Chandreyee
C
White
Eileen
E
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D017124:Conserved Sequence; D017931:DNA Primers; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D017433:Protein Structure, Secondary; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D017931:DNA Primers; D009363:Neoplasm Proteins; C497336:RHOBTB2 protein, human; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D019204:GTP-Binding Proteins