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JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells

Dharminder Chauhan1, Guilan Li, Teru Hideshima

  • 1Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|April 1, 2003
PubMed

Insights

The c-Jun NH(2)-terminal kinase (JNK) pathway is crucial for releasing Smac (second mitochondria-derived activator of caspases) from mitochondria during apoptosis in multiple myeloma cells, initiating programmed cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Smac (second mitochondria-derived activator of caspases) is a key protein promoting apoptosis by activating caspases.
  • The role of c-Jun NH(2)-terminal kinase (JNK) in Smac release during apoptosis remains unclear.
  • Previous research links JNK to cytochrome c regulation in apoptosis.

Purpose of the Study:

  • To investigate the role of JNK in the mitochondrial release of Smac during apoptosis in multiple myeloma (MM) cells.
  • To determine if JNK activation is necessary for Smac release and subsequent apoptosis induction.

Main Methods:

  • Induction of apoptosis in multiple myeloma cells.
  • Analysis of JNK activation and translocation.
  • Assessment of Smac release from mitochondria.
  • Inhibition of JNK using a dominant-negative mutant (DN-JNK) and a specific inhibitor (SP600125).

Main Results:

  • Apoptosis induction in MM cells correlated with JNK activation and its translocation to mitochondria.
  • JNK translocation preceded the release of Smac from mitochondria to the cytosol.
  • Inhibition of JNK signaling abrogated both Smac release and apoptosis.
  • Blocking JNK prevented stress-induced Smac release and apoptosis.

Conclusions:

  • JNK activation is an essential event for Smac release during stress-induced apoptosis in multiple myeloma cells.
  • JNK signaling pathway plays a critical role in regulating mitochondrial Smac release, a key step in apoptosis.

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