Abstract
We report here that the Jun dimerization protein 2 (JDP2) plays a critical role as a cofactor for the transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and MafK in the regulation of the antioxidants and production of reactive oxygen species (ROS). JDP2 associates with Nrf2 and MafK (Nrf2-MafK) to increase the transcription of antioxidant response element-dependent genes. Oxidative-stress-inducing reagent led to an increase in the intracellular accumulation of ROS and cell proliferation in Jdp2 knock-out mouse embryonic fibroblasts. In Jdp2-Cre mice mated with reporter mice, the expression of JDP2 was restricted to granule cells in the brain cerebellum. The induced pluripotent stem cells (iPSC)-like cells were generated from DAOY medulloblastoma cell by introduction of JDP2, and the defined factor OCT4. iPSC-like cells expressed stem cell-like characteristics including alkaline phosphatase activity and some stem cell markers. However, such iPSC-like cells also proliferated rapidly, became neoplastic, and potentiated cell malignancy at a later stage in SCID mice. This study suggests that medulloblastoma cells can be reprogrammed successfully by JDP2 and OCT4 to become iPSC-like cells. These cells will be helpful for studying the generation of cancer stem cells and ROS homeostasis.
Highlights
Oxidative stress can be induced by a vast range of agents, including xenobiotic, drugs, heavy metals, and ionizing radiation, and can lead to the generation of reactive oxygen species (ROS) and electrophiles
Jun dimerization protein 2 (JDP2) acts as an AP-1 repressor protein to suppress cell proliferation during cancer progression and participates in the maintenance of ROS homeostasis to prevent cell damage by ROS
We generated induced pluripotent stem cells (iPSC)-like cells form DAOY medulloblastoma cell by introducing JDP2 and the defining factor OCT4. iPSC-like cells expressed stem cell-like characteristics including alkaline phosphatase and some stem cell markers
Summary
Oxidative stress can be induced by a vast range of agents, including xenobiotic, drugs, heavy metals, and ionizing radiation, and can lead to the generation of reactive oxygen species (ROS) and electrophiles. ROS often contribute to diseases such as cancer, cardiovascular complications, acute and chronic inflammation, and neurodegenerative condition [1,2]. Cellular defense mechanisms are required to control constantly the levels of ROS and to prevent their accumulation. Many antioxidant and/or detoxification enzymes, such as NADPH: quinone oxidoreductase 1 (NQO1) [3,4], glutathione S-transferase (GST) [5], and heme oxygenase-1 (HO-1) [6] contribute to cellular defenses systems against ROS. The coordinated induction of the genes encoding the Phase II detoxification and antioxidant enzymes is governed by the core sequence 5'-G/A TGACNNNGC-3' located in their gene regulatory regions, and is termed the antioxidant responsive element (ARE) [7].
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