JNK2 up-regulates hypoxia-inducible factors and contributes to hypoxia-induced erythropoiesis and pulmonary hypertension

Marc A. Sala, Cong Chen, Qiao Zhang, Hanh Chi Do-Umehara, Wenjiao Wu, Alexander V. Misharin, Gregory B. Waypa, Deyu Fang, G. R.Scott Budinger, Shuwen Liu, Navdeep S. Chandel, Paul T. Schumacker, Jacob I. Sznajder, Jing Liu*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1α and HIF-2α and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1α in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1α and HIF-2α mRNAlevels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies.

Original languageEnglish (US)
Pages (from-to)271-284
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Hypoxia-Inducible Factor 1
Erythropoiesis
Pulmonary Hypertension
Up-Regulation
Protein Kinases
Protein Isoforms
Pathology
Erythropoietin
Polycythemia
Genes
Cells
Tissue
Oxygen
Hypoxia
Cell Hypoxia
JNK Mitogen-Activated Protein Kinases
endothelial PAS domain-containing protein 1
Ventricular Pressure
Heat-Shock Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "JNK2 up-regulates hypoxia-inducible factors and contributes to hypoxia-induced erythropoiesis and pulmonary hypertension",
abstract = "The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1α and HIF-2α and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1α in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1α and HIF-2α mRNAlevels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies.",
author = "Sala, {Marc A.} and Cong Chen and Qiao Zhang and Do-Umehara, {Hanh Chi} and Wenjiao Wu and Misharin, {Alexander V.} and Waypa, {Gregory B.} and Deyu Fang and Budinger, {G. R.Scott} and Shuwen Liu and Chandel, {Navdeep S.} and Schumacker, {Paul T.} and Sznajder, {Jacob I.} and Jing Liu",
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TY - JOUR

T1 - JNK2 up-regulates hypoxia-inducible factors and contributes to hypoxia-induced erythropoiesis and pulmonary hypertension

AU - Sala, Marc A.

AU - Chen, Cong

AU - Zhang, Qiao

AU - Do-Umehara, Hanh Chi

AU - Wu, Wenjiao

AU - Misharin, Alexander V.

AU - Waypa, Gregory B.

AU - Fang, Deyu

AU - Budinger, G. R.Scott

AU - Liu, Shuwen

AU - Chandel, Navdeep S.

AU - Schumacker, Paul T.

AU - Sznajder, Jacob I.

AU - Liu, Jing

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1α and HIF-2α and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1α in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1α and HIF-2α mRNAlevels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies.

AB - The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1α and HIF-2α and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1α in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1α and HIF-2α mRNAlevels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies.

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U2 - 10.1074/jbc.RA117.000440

DO - 10.1074/jbc.RA117.000440

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JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

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