TXNIP Maintains the Hematopoietic Cell Pool by Switching the Function of p53 under Oxidative Stress

Abstract

Reactive oxygen species (ROS) are critical determinants of the fate of hematopoietic stem cells (HSCs) and hematopoiesis. Thioredoxin-interacting protein (TXNIP), which is induced by oxidative stress, is a known regulator of intracellular ROS. Txnip(-/-) old mice exhibited elevated ROS levels in hematopoietic cells and showed a reduction in hematopoietic cell population. Loss of TXNIP led to a dramatic reduction of mouse survival under oxidative stress. TXNIP directly regulated p53 protein by interfering with p53- mouse double minute 2 (MDM2) interactions and increasing p53 transcriptional activity. Txnip(-/-) mice showed downregulation of the antioxidant genes induced by p53. Introduction of TXNIP or p53 into Txnip(-/-) bone marrow cells rescued the HSC frequency and greatly increased survival in mice following oxidative stress. Overall, these data indicate that TXNIP is a regulator of p53 and plays a pivotal role in the maintenance of the hematopoietic cells by regulating intracellular ROS during oxidative stress.

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…The expression levels were determined by western blotting and statistical analysis (Figure 1f,g and Supporting Information Figure S5) or quantitative real‐time PCR (Supporting Information Figure S1A,B). We previously reported the regulation of p53 by TXNIP (Jung et al, 2013). To examine the effects of p53 on the cellular senescence, we prepared WT, KO, p53 ‐/‐ , and TXNIP ‐/‐ p53 ‐/‐ (DKO) MEF cells.…”

“…However, the interaction of TXNIP and AKT was upregulated by glucose and H 2 O 2 treatment (Figure 3), implying that TXNIP may negatively regulate AKT activity under glucose stress and oxidative stress. We previously reported that TXNIP deficiency induced premature aging phenotypes of HSCs in aged mice by increasing ROS levels in vitro and in vivo (Jung et al, 2016, 2013 ). Next, we analyzed the metabolic characterization of WT and KO mice to determine the effect of TXNIP on the aging of mice.…”

“…In our previous reports, we found that TXNIP interacts with p53, p38 MAPK, and macrophage migration inhibitory factor (MIF) and regulates their functional activity (Jung et al, 2016, 2013; Kim et al, 2017). TXNIP stabilized p53 protein via direct interaction, and TXNIP acted as a functional switch of p53 to regulate ROS level in hematopoietic cells.…”

“…TXNIP is an α‐arrestin family protein that is induced by a rise in glucose and oxidative stress and is known to be a tumor suppressor and inhibit thioredoxin (TRX), an antioxidant protein, via a direct interaction (DeBalsi et al, 2014; Jung et al, 2016, 2013 ). Many studies have examined the role of TXNIP in glucose uptake and metabolism.…”

“…TXNIP expression is related to mitochondrial fuel switching under conditions of starvation, diabetes, and exercise in skeletal muscle (DeBalsi et al, 2014). Previously, we suggested that TXNIP is highly expressed and acts as an antioxidant protein to regulate cellular ROS by activating p53 activity or by inhibiting p38 mitogen‐activated protein kinase (MAPK) activity via direct interaction in hematopoietic stem cells (HSCs) (Jung & Choi, 2014; Jung et al, 2016, 2013 ). Importantly, TXNIP‐deficient mice are more glucose‐tolerant than wild‐type (WT) mice (Hui et al, 2008).…”