Abstract
The promyelocytic leukemia (PML) tumor suppressor is a pleiotropic modulator of apoptosis. However, the molecular basis for such a diverse proapoptotic role is currently unknown. We show that extranuclear Pml was specifically enriched at the endoplasmic reticulum (ER) and at the mitochondria-associated membranes, signaling domains involved in ER-to-mitochondria calcium ion (Ca(2+)) transport and in induction of apoptosis. We found Pml in complexes of large molecular size with the inositol 1,4,5-trisphosphate receptor (IP(3)R), protein kinase Akt, and protein phosphatase 2a (PP2a). Pml was essential for Akt- and PP2a-dependent modulation of IP(3)R phosphorylation and in turn for IP(3)R-mediated Ca(2+) release from ER. Our findings provide a mechanistic explanation for the pleiotropic role of Pml in apoptosis and identify a pharmacological target for the modulation of Ca(2+) signals.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Adenosine Triphosphate / metabolism
- Animals
- Apoptosis*
- Calcium / metabolism*
- Calcium Signaling*
- Cell Line
- Cell Nucleus / metabolism
- Cells, Cultured
- Cytosol / metabolism
- Endoplasmic Reticulum / metabolism*
- Homeostasis
- Humans
- Inositol 1,4,5-Trisphosphate / metabolism
- Inositol 1,4,5-Trisphosphate Receptors / metabolism
- Intracellular Membranes / metabolism
- Mice
- Mitochondria / metabolism
- Nuclear Proteins / genetics
- Nuclear Proteins / metabolism*
- Phosphorylation
- Promyelocytic Leukemia Protein
- Protein Phosphatase 2 / metabolism
- Proto-Oncogene Proteins c-akt / metabolism
- Recombinant Fusion Proteins / metabolism
- Stress, Physiological
- Transcription Factors / genetics
- Transcription Factors / metabolism*
- Tumor Suppressor Proteins / genetics
- Tumor Suppressor Proteins / metabolism*
Substances
- Inositol 1,4,5-Trisphosphate Receptors
- Nuclear Proteins
- Pml protein, mouse
- Promyelocytic Leukemia Protein
- Recombinant Fusion Proteins
- Transcription Factors
- Tumor Suppressor Proteins
- Inositol 1,4,5-Trisphosphate
- Adenosine Triphosphate
- Proto-Oncogene Proteins c-akt
- Protein Phosphatase 2
- Calcium