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PML regulates apoptosis at endoplasmic reticulum by modulating calcium release

Carlotta Giorgi1, Keisuke Ito, Hui-Kuan Lin

  • 1Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Emilia Romagna Laboratory BioPharmaNet, and Laboratory for Technologies of Advanced Therapies (LTTA) University of Ferrara, Ferrara, Italy.

Science (New York, N.Y.)
|October 30, 2010
PubMed

Insights

The promyelocytic leukemia (PML) protein regulates apoptosis by interacting with key signaling molecules at the endoplasmic reticulum and mitochondria. This interaction controls calcium ion release, explaining PML's diverse roles in programmed cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The promyelocytic leukemia (PML) protein is a known tumor suppressor with diverse roles in apoptosis.
  • The precise molecular mechanisms underlying PML's pleiotropic proapoptotic functions remain largely unelucidated.

Purpose of the Study:

  • To investigate the molecular basis for the promyelocytic leukemia (PML) protein's diverse proapoptotic functions.
  • To identify the cellular localization and interacting partners of PML involved in apoptosis regulation.

Main Methods:

  • Subcellular fractionation to isolate endoplasmic reticulum (ER) and mitochondria-associated membranes.
  • Co-immunoprecipitation assays to identify protein complexes.
  • Western blotting and phospho-specific antibodies to assess protein phosphorylation.
  • Calcium imaging to measure intracellular calcium ion (Ca(2+)) flux.

Main Results:

  • Extranuclear PML localizes to the endoplasmic reticulum and mitochondria-associated membranes, critical sites for calcium signaling and apoptosis.
  • PML forms large molecular complexes with the inositol 1,4,5-trisphosphate receptor (IP(3)R), Akt kinase, and PP2a phosphatase.
  • PML is essential for the Akt- and PP2a-mediated regulation of IP(3)R phosphorylation, controlling ER calcium release.

Conclusions:

  • PML's extranuclear localization and interaction with IP(3)R, Akt, and PP2a provide a mechanistic explanation for its pleiotropic role in apoptosis.
  • The findings identify a novel pathway for regulating calcium signaling and suggest a potential pharmacological target for modulating apoptosis.

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