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Redox Regulation of the Embryonic Stem Cell Transcription Factor Oct-4 by Thioredoxin

^a The Walther Oncology Center,
^b Department of Pediatrics and Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis, Indiana;
^c Department of Anesthesia, Kyoto University Hospital, and the Institute for Virus Research, Kyoto University, Kyoto, Japan;
^d The Center for Animal Transgenesis and Germ Cell Research, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
^e Department of Internal Medicine, and the Cancer Treatment and Research Center, the University of New Mexico, Albuquerque, New Mexico

Key Words. Embryonic stem cells • Transcription factors • Differentiation • Oxidation

Robert Hromas, M.D., Department of Internal Medicine, and the Cancer Treatment and Research Center, University of New Mexico, 900 Camino de Salud, Albuquerque, New Mexico 87131, USA. Telephone: 505-272-5837; Fax: 505-272-5865; email: rhromas{at}salud.unm.edu

Oct-4 is a transcriptional regulator required to maintain the totipotentiality of embryonic stem (ES) cells. Downregulation of its activity is required for proper differentiation of the blastocyst during uterine implantation. Uterine implantation and subsequent vascularization increase oxygen exposure of the developing embryo, thereby altering the intracellular reduction-oxidation status. We tested whether Oct-4 could be regulated by these changes in reduction-oxidation status. We found that Oct-4 DNA binding was exquisitely sensitive to abrogation by oxidation but that the DNA binding of another ES cell transcription factor, FoxD3, was much less sensitive to oxidation. The reducing enzyme Thioredoxin (but not Ape-1) could restore DNA-binding activity of Oct-4. Thioredoxin was less effective at restoring the DNA-binding ability of FoxD3. It was also found that Thioredoxin (but not Ape-1) could physically associate with cysteines in the POU domain of Oct-4. Finally, overexpressing normal Thioredoxin increased the transcriptional activity of Oct-4, while overexpressing a mutant Thioredoxin decreased the transcriptional activity of Oct-4. These data imply that ES cell transcription factors are differentially sensitive to oxidation and that Thioredoxin may differentially regulate ES cell transcription factors.

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