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PMID:21030605

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Citation

Giorgi, C, Ito, K, Lin, HK, Santangelo, C, Wieckowski, MR, Lebiedzinska, M, Bononi, A, Bonora, M, Duszynski, J, Bernardi, R, Rizzuto, R, Tacchetti, C, Pinton, P and Pandolfi, PP (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247-51

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.

Links

PubMed PMC3017677 Online version:10.1126/science.1189157

Keywords

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; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:AKT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70227

F

Seeded From UniProt

complete

MOUSE:ITPR3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31750

F

Seeded From UniProt

complete

MOUSE:ITPR3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q60953

F

Seeded From UniProt

complete

MOUSE:ITPR3

located_in

GO:0005789: endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ITPR3

involved_in

GO:0060402: calcium ion transport into cytosol

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PML

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70227

F

Seeded From UniProt

complete

MOUSE:PML

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PML

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PML

located_in

GO:0042406: extrinsic component of endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PML

acts_upstream_of_or_within

GO:0070059: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PML

involved_in

GO:0001932: regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PML

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PML

acts_upstream_of_or_within

GO:0008631: intrinsic apoptotic signaling pathway in response to oxidative stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PML

part_of

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PML

involved_in

GO:0010522: regulation of calcium ion transport into cytosol

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PML

involved_in

GO:0032469: endoplasmic reticulum calcium ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PML

part_of

GO:0042406: extrinsic component of endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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