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The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis

P Mehlen1, S Rabizadeh, S J Snipas

  • 1Program on Aging, The Burnham Institute, La Jolla, California 92037, USA.

Nature
|October 31, 1998
PubMed

Insights

The deleted in colorectal cancer (DCC) gene suppresses tumors by inducing apoptosis when its ligand, netrin-1, is absent. DCC cleavage by caspase-3 is essential for this tumor-suppressive function.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell signaling

Background:

  • Colorectal cancer development involves gene mutations, including the candidate tumor suppressor DCC.
  • DCC encodes the netrin-1 receptor, crucial for axon guidance.
  • Loss of DCC expression correlates with tumorigenicity, but its mechanism remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which DCC suppresses tumor formation.
  • To investigate the role of netrin-1 binding and caspase cleavage in DCC function.

Main Methods:

  • Investigated DCC's effect on apoptosis with and without netrin-1.
  • Identified DCC as a caspase substrate.
  • Mutated the caspase-3 cleavage site on DCC to assess its impact on apoptosis.

Main Results:

  • DCC induces apoptosis independently of netrin-1 binding.
  • Netrin-1 binding to DCC inhibits apoptosis.
  • Cleavage of DCC by caspase-3 is required for its pro-apoptotic activity, specifically at Asp 1,290.

Conclusions:

  • DCC functions as a tumor suppressor by promoting apoptosis when netrin-1 is unavailable.
  • This pro-apoptotic function is mediated by caspase cascades and requires DCC cleavage at Asp 1,290.
  • DCC's mechanism involves ligand-independent apoptosis induction via caspase-mediated cleavage, crucial for tumor suppression.

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