Tat-DJ-1 inhibits oxidative stress-mediated RINm5F cell death through suppression of NF-κB and MAPK activation.

Hyo Sang Jo,Won Sik Eum,Hyun Ju Cha,Yeon Joo Choi,Chi Hern Lee,Sang Jin Kim,Jung Hwan Park,Su Bin Cho,Eun Ji Yeo,Hyeon Ji Yeo,Soo Young Choi

doi:10.1007/s00044-016-1698-4

Hyo Sang Jo, Won Sik Eum + Show 9 more

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https://doi.org/10.1007/s00044-016-1698-4

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Oxidative stress is highly involved in the development of diabetes mellitus by destruction of pancreatic β-cells. DJ-1 is an antioxidant protein and DJ-1 expression levels are known to be reduced in diabetes mellitus. Thus, we examined the effects of DJ-1 protein against oxidative stress-induced pancreatic β-cell (RINm5F) death using cell permeable wild-type and mutant-type (C106A) Tat-DJ-1 proteins, which both efficiently transduced into RINm5F cells. Intracellular stability of wild-type Tat-DJ-1 persisted two times longer than C106A Tat-DJ-1. Wild-type Tat-DJ-1 protein markedly protected cells from hydrogen peroxide-induced toxicities such as cell death, reactive oxygen species generation, and DNA fragmentation. Further, wild-type Tat-DJ-1 protein significantly inhibited hydrogen peroxide-induced activation of mitogen-activated protein kinases and NF-κB signaling. On the other hand, C106A Tat-DJ-1 protein did not show the same protective effects. These results indicate that wild-type Tat-DJ-1 inhibits oxidative stress-induced cellular toxicity and activation of mitogen-activated protein kinases and NF-κB signals in RINm5F cells. These results suggest that wild-type Tat-DJ-1 protein may be a potential therapeutic agent against diabetes mellitus or toward the prevention of pancreatic β-cell destruction.

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Oxidative stress-induced cellular reactive oxygen species (ROS) are highly associated with pancreatic β-cell death, since antioxidant protein expression levels are very low in pancreatic β-cells which leaves them more susceptible to ROS in comparison to other tissues (Lenzen et al, 1996; Suarez-Pinzon et al, 1997; Tabatabaie et al, 2003)
Numerous studies have revealed that therapeutic proteins, when fused with protein transduction domains (PTDs), transduce into various cells and prevent against oxidative stressinduced cell death in vitro and in vivo (Wadia and Dowdy, 2002; Kubo et al, 2008; Dietz, 2010; van den Berg and Dowdy, 2011; Zhang et al, 2014; Kim et al, 2015a, b)
We prepared cell permeable WT and mutant-type (C106A) Tat-DJ-1 proteins in order to examine the effects of Tat-DJ-1 proteins on pancreatic RINm5F cells

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Introduction

Oxidative stress-induced cellular reactive oxygen species (ROS) are highly associated with pancreatic β-cell death, since antioxidant protein expression levels are very low in pancreatic β-cells which leaves them more susceptible to ROS in comparison to other tissues (Lenzen et al, 1996; Suarez-Pinzon et al, 1997; Tabatabaie et al, 2003). Other studies have demonstrated that increased cellular ROS levels lead to pancreatic β-cell destruction, while overexpressed antioxidant proteins inhibit oxidative stressinduced pancreatic β-cell death (Hohmeier et al, 1998; Tiedge et al, 1998; Tiedge et al, 1999; Lee et al, 2015). Delivery of proteins into cells was achieved using protein transduction domains (PTDs), which, when fused with therapeutic proteins, can deliver those proteins into cells (Kim et al, 2013; Lee et al, 2015). These studies suggest that the regulation of ROS production plays a crucial role against oxidative stress-induced pancreatic β-cell death.

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