Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase

Jinwook Shin, Boyoun Park, Sunglim Cho, Sunray Lee, Youngkyun Kim, Seong Ok Lee, Kwangmin Cho, Sungwook Lee, Bong Suk Jin, Jin Hyun Ahn, Eui Ju Choi, Kwangseog Ahn

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 NH2-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.

Original languageEnglish
Pages (from-to)40994-41003
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number39
DOIs
Publication statusPublished - 2004 Sep 24

Fingerprint

Mitogen-Activated Protein Kinase 11
p38 Mitogen-Activated Protein Kinases
Leukemia
Genes
Tumor Suppressor Proteins
Cell death
Apoptosis
Cell Death
Phosphotransferases

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shin, Jinwook ; Park, Boyoun ; Cho, Sunglim ; Lee, Sunray ; Kim, Youngkyun ; Lee, Seong Ok ; Cho, Kwangmin ; Lee, Sungwook ; Jin, Bong Suk ; Ahn, Jin Hyun ; Choi, Eui Ju ; Ahn, Kwangseog. / Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 39. pp. 40994-41003.
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abstract = "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 NH2-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.",
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Shin, J, Park, B, Cho, S, Lee, S, Kim, Y, Lee, SO, Cho, K, Lee, S, Jin, BS, Ahn, JH, Choi, EJ & Ahn, K 2004, 'Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase', Journal of Biological Chemistry, vol. 279, no. 39, pp. 40994-41003. https://doi.org/10.1074/jbc.M407369200

Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase. / Shin, Jinwook; Park, Boyoun; Cho, Sunglim; Lee, Sunray; Kim, Youngkyun; Lee, Seong Ok; Cho, Kwangmin; Lee, Sungwook; Jin, Bong Suk; Ahn, Jin Hyun; Choi, Eui Ju; Ahn, Kwangseog.

In: Journal of Biological Chemistry, Vol. 279, No. 39, 24.09.2004, p. 40994-41003.

Research output: Contribution to journalArticle

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T1 - Promyelocytic leukemia is a direct inhibitor of SAPK2/p38 mitogen-activated protein kinase

AU - Shin, Jinwook

AU - Park, Boyoun

AU - Cho, Sunglim

AU - Lee, Sunray

AU - Kim, Youngkyun

AU - Lee, Seong Ok

AU - Cho, Kwangmin

AU - Lee, Sungwook

AU - Jin, Bong Suk

AU - Ahn, Jin Hyun

AU - Choi, Eui Ju

AU - Ahn, Kwangseog

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N2 - 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 NH2-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.

AB - 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 NH2-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.

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