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A novel isoform of prostate apoptosis response 4 (PAR-4) that co-distributes with F-actin and prevents apoptosis in

G Wang1, J Silva, K Krishnamurthy

  • 1Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, 1120 15th Street Room CB-2803, Augusta, GA 30912, USA.

Apoptosis : an International Journal on Programmed Cell Death
|March 8, 2006
PubMed

Insights

A novel prostate apoptosis response-4 (PAR-4) isoform, PAR-4/p33, inhibits apoptosis by preventing the full-length PAR-4/p38 from entering the nucleus. This discovery reveals a new regulator of PAR-4-dependent cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Developmental Biology

Background:

  • Prostate apoptosis response-4 (PAR-4) induces apoptosis in differentiating mouse embryonic stem cells.
  • PAR-4 exists as 38 kDa and 33 kDa isoforms in embryoid body cells and embryonic mouse brain.

Purpose of the Study:

  • To clone and characterize a novel PAR-4 isoform.
  • To investigate the function and cellular localization of PAR-4 isoforms.
  • To elucidate the regulatory mechanism of PAR-4-dependent apoptosis.

Main Methods:

  • Cloning and characterization of a novel PAR-4 isoform (PAR-4/p33) from mouse embryoid body-derived RNA.
  • Expression of fluorescent fusion proteins of PAR-4 isoforms.
  • Analysis of protein localization (cytosol vs. nucleus) and co-distribution with F-actin.
  • Assessment of caspase 3 activation and apoptosis induction upon ectopic expression.
  • Investigation of protein complex formation between PAR-4 isoforms.

Main Results:

  • A novel PAR-4 isoform, PAR-4/p33, lacking exon 3, was identified and characterized.
  • PAR-4/p33 localizes to the cytosol and co-distributes with F-actin, while full-length PAR-4/p38 localizes to the nucleus.
  • Ectopic expression of PAR-4/p33 does not induce apoptosis or activate caspase 3.
  • PAR-4/p33 forms a complex with PAR-4/p38, inhibiting its nuclear translocation and subsequent apoptosis induction.

Conclusions:

  • PAR-4/p33 acts as a dominant-negative isoform of PAR-4/p38.
  • PAR-4/p33 regulates PAR-4-dependent apoptosis by sequestering PAR-4/p38 in the cytosol.
  • This finding provides new insights into the regulation of apoptosis during cellular differentiation.

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