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 mRNA levels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (). 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.

Identifying Candidate Genes for Hypoxia Adaptation of Tibet Chicken Embryos by Selection Signature Analyses and RNA Sequencing

“…The 40 genes differentially expressed in the heart were enriched into three GO terms (GO:0046329 ~ negative regulation of JNK cascade; GO:0016477 ~ cell migration; GO:0001046 ~ core promoter sequence-specific DNA binding). JNK (c-Jun N-terminal protein kinase) is a class of stress-activated protein kinase, and its activation induced by hypoxia is an early response to hypoxic stress [ 71 , 72 ]. It was reported that JNK2 upregulated HIFs (Hypoxia Inducible Factors) and contributed to pulmonary hypertension and polycythemia induced by hypoxia [ 72 ].…”

Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma

“…Recently, it was shown that deubiquitylase Cezanne (also known as OTUD7B) regulates HIF2A expression via transcription factor E2F1 that directly affects the HIF2A gene expression (21). Moreover, poly (ADP-ribose) polymerase-1 (PARP-1) and JNK2 has been reported to regulate HIF2A expression level (22,23). Also, insulin-like growth factor 2 (IGF2)-induced PI3K-mTORC2 signaling was shown to regulate HIF2A mRNA expression in neuroblastoma cells (24).…”

JNK2 regulates vascular remodeling in pulmonary hypertension

“…recently reported that JNK2 may play a role in the development of hypoxia-induced PH since mice deficient in JNK2 are relatively (but not completely) spared from hypoxia-induced PH. 11 …”

“…To test our hypothesis, we evaluated whether PH pathology is associated with the activation of JNK1/2 using lung tissues from healthy humans and PH patients as well as lung tissues from a well-established bovine model of severe hypoxic PH. Since loss-of-function studies in mice have provided major insights into the function of JNK isoforms in development and disease, 11 , 15 we then used JNK1 and JNK2 null mice to evaluate further the role of each individual isoform in the molecular mechanisms driving the development and progression of PH. For that, wild-type (WT), JNK1 -/- , and JNK2 -/- mice were exposed to either room air (normoxia) or 10% O 2 (hypoxia) for six weeks to induce PH.…”