Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase.
The promyelocytic leukemia gene (PML) encodes a growth/tumor suppressor protein that is essential for the induction of apoptosis in response to various apoptotic signals. The mechanism by which PML plays a role in the regulation of cell death is still unknown. In the current study, we demonstrate that PML negatively regulated the SAPK2/p38 signaling pathway by sequestering p38 from its upstream kinases, MKK3, MKK4, and MKK6, whereas PML did not affect the SAPK1/c-Jun NH(2)-terminal kinase pathway. PML associated with p38 both in vitro and in vivo and the carboxyl terminus of PML mediated the interaction. In contrast to other studies of PML and PML-nuclear bodies (NB), our study shows that the formation of PML-NBs was not required for PML to suppress p38 activity because PML was still able to bind and inhibit p38 activity under the conditions in which PML-NBs were disrupted. In addition, we show that the promotion of Fas-induced cell death by PML correlated with the extent of p38 inhibition by PML, suggesting that PML might regulate apoptosis through manipulating SAPK2/p38 pathways. Our findings define a novel function of PML as a negative regulator of p38 kinase and provide further understanding on the mechanism of how PML induces multiple pathways of apoptosis.
College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Jinwook
J
Shin
Boyoun
B
Park
Sunglim
S
Cho
Sunray
S
Lee
Youngkyun
Y
Kim
Seong-Ok
SO
Lee
Kwangmin
K
Cho
Sungwook
S
Lee
Bong-Suk
BS
Jin
Jin-Hyun
JH
Ahn
Eui-Ju
EJ
Choi
Kwangseog
K
Ahn
D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011725:Pyridines; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C070576:PML protein, human; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580