PML regulates apoptosis at endoplasmic reticulum by modulating calcium release.

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 showthat extranuclear Pml was specifically enriched at the endoplasmic reticulum (ER) and at themitochondria-associated membranes, signaling domains involved in ER-to-mitochondria calciumion (Ca2+) transport and in induction of apoptosis. We found Pml in complexes of large molecularsize with the inositol 1,4,5-trisphosphate receptor (IP3R), protein kinase Akt, and proteinphosphatase 2a (PP2a). Pml was essential for Akt- and PP2a-dependent modulation of IP3Rphosphorylation and in turn for IP3R-mediated Ca2+ release from ER. Our findings provide amechanistic explanation for the pleiotropic role of Pml in apoptosis and identify a pharmacologicaltarget for the modulation of Ca2+ signals.