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Caspase-dependent processing activates the proapoptotic activity of deleted in breast cancer-1 during tumor necrosis

Ramya Sundararajan1, Guanghua Chen, Chandreyee Mukherjee

  • 1Rutgers University, 679 Hoes Lane, Room 140, Piscataway, NJ 08854, USA.

Oncogene
|April 13, 2005
PubMed

Insights

Deleted in breast cancer-1 (DBC-1) protein is processed by caspases during tumor necrosis factor (TNF)-alpha-induced apoptosis. This processing promotes cell death and may contribute to tumor suppression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Deleted in breast cancer-1 (DBC-1) is a protein encoded by a gene located on human chromosome 8p21, a region frequently deleted in various cancers.
  • The precise function of DBC-1 and its role in cellular processes, particularly apoptosis, remained largely unknown.

Purpose of the Study:

  • To investigate the function of DBC-1 during tumor necrosis factor (TNF)-alpha-mediated apoptosis.
  • To elucidate the processing and localization of DBC-1 in response to apoptotic stimuli.

Main Methods:

  • Analysis of DBC-1 processing during TNF-alpha-induced apoptosis using Western blotting and caspase activity assays.
  • Subcellular localization studies of endogenous and overexpressed DBC-1.
  • Functional assays involving overexpression of DBC-1 fragments to assess effects on apoptosis and mitochondrial morphology.

Main Results:

  • Full-length DBC-1 (150 kDa) undergoes caspase-dependent cleavage during TNF-alpha-mediated apoptosis, generating carboxy-terminal fragments (p120 DBC-1 and p66 DBC-1).
  • DBC-1 translocates from the nucleus to the cytoplasm during apoptosis, correlating with the loss of its amino-terminal nuclear localization signal.
  • Overexpression of an amino-terminal truncated DBC-1 fragment induces mitochondrial clustering and condensation, sensitizing cells to TNF-alpha-induced apoptosis.
  • The carboxy-terminal coiled-coil domain of DBC-1 mediates its cytoplasmic localization and pro-apoptotic activity.

Conclusions:

  • Caspase-dependent processing of DBC-1 serves as a feed-forward mechanism to enhance apoptosis.
  • DBC-1 processing and subsequent cytoplasmic localization may contribute to tumor suppression.
  • DBC-1, similar to its homolog CARP-1, plays a role in the regulation of apoptosis.

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