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International Journal Of Bilogical Sciences

.: Home > International Journal Of Bilogical Sciences > 2016 > Volume 12 Number 2 > Hye Jung Baek, Yong Min Lee, Tae Hyun Kim, Joo-Young Kim, Eun Jung Park, Kuniyoshi Iwabuchi, Lopa Mishra, Sang Soo Kim

Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage

Hye Jung Baek, Yong Min Lee, Tae Hyun Kim, Joo-Young Kim, Eun Jung Park, Kuniyoshi Iwabuchi, Lopa Mishra, Sang Soo Kim
1. Radiation Medicine Branch, and 2. Cancer Immunology Branch, National Cancer Center, Goyang, Gyeonggi, 410-769, Korea, 3. Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Kahoku-gun, Ishikawa, 920-0293, Japan. 4. Department of Gastroenterology, Hepatology, and Nutrition, MD Anderson Cancer Center, Houston, Texas, 77030, USA  Corresponding author: Sang Soo Kim, Radiation Medicine Branch, National Cancer Center, Goyang, Gyeonggi, 410-769, Korea. Tel: 8231-920-2491, Fax: 8231-920-2494, E-mail: sangsookim@ncc.re.kr
Abstract :

The ubiquitously expressed β2-spectrin (β2SP, SPTBN1) is the most common non-erythrocytic member of the β-spectrin gene family. Loss of β2-spectrin leads to defects in liver development, and its haploinsufficiency spontaneously leads to chronic liver disease and the eventual development of hepatocellular cancer. However, the specific role of β2-spectrin in liver homeostasis remains to be elucidated. Here, we reported that β2-spectrin was cleaved by caspase-3/7 upon treatment with acetaminophen which is the main cause of acute liver injury. Blockage of β2-spectrin cleavage robustly attenuated β2-spectrin-specific functions, including regulation of the cell cycle, apoptosis, and transcription. Cleaved fragments of β2-spectrin were physiologically active, and the N- and C-terminal fragments retained discrete interaction partners and activity in transcriptional regulation and apoptosis, respectively. Cleavage of β2-spectrin facilitated the redistribution of the resulting fragments under conditions of liver damage induced by acetaminophen. In contrast, downregulation of β2-spectrin led to resistance to acetaminophen-induced cytotoxicity, and its insufficiency in the liver promoted suppression of acetaminophen-induced liver damage and enhancement of liver regeneration. Conclusions: β2-Spectrin, a TGF-β mediator and signaling molecule, is cleaved and activated by caspase-3/7, consequently enhancing apoptosis and transcriptional control to determine cell fate upon liver damage. These findings have extended our knowledge on the spectrum of β2-spectrin functions from a scaffolding protein to a target and transmitter of TGF-β in liver damage.

Keywords :
β2-spectrin, acetaminophen, TGF-β, caspase-3/7, liver damage

Date Deposited : 15 Mar 2016 13:13

Last Modified : 15 Mar 2016 13:13

Official URL: http://www.ijbs.com/v12i2

Volume 12, Number 2, - 2016 , ISSN 1449-2288

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