Induction of apoptosis by the overexpression of an alternative splicing variant of mitochondrial thioredoxin reductase.
Mammalian cells harbor two forms of thioredoxin reductase (TrxR), cytosolic TrxR1 and mitochondrial TrxR2, both of which are involved in the redox regulation of cell growth and apoptosis. Furthermore, several alternative splicing variants of TrxR1 and TrxR2 have been identified. However, little remains known with regard to their functions in cells. Here, we report an alternative splicing variant of TrxR2 (TrxR2A), which displays a 3-bp deletion in the coding region and an insertion of 1228 bp in the 3'-UTR, between the stop codon and the SECIS element, of the TrxR2 cDNA. In order to determine the cellular function of TrxR2A, we established TrxR2A-inducible HeLa cell lines in which TrxR2A transcription was regulated via a Tet-off expression system. We observed that the induction of TrxR2A resulted in increased apoptosis, due to the reduction of NADPH and alterations in cellular ROS levels. These results suggest that TrxR2A may play a vital role in the regulation of TrxR2 and may confer functional complexity onto the thioredoxin system.
Chang
En Young
EY
Department of Biochemistry and Molecular Biology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, 317-1 Daemyong-Dong, Daegu 705-717, Republic of Korea.
Son
Seong-Kweon
SK
Ko
Hyun Sook
HS
Baek
Suk-Hwan
SH
Kim
Jung Hye
JH
Kim
Jae-Ryong
JR
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular; D053938:DNA Fragmentation / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D009249:NADP / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
D018076:DNA, Complementary; D017382:Reactive Oxygen Species; D009249:NADP; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase; D013752:Tetracycline