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 journalArticlepeer-review

10 Scopus citations


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
Issue number1
StatePublished - Jan 5 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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