Oct 4 is Critical for Survival/Antiapoptosis of Murine Embryonic Stem Cells Subjected to Stress. Effects Associated with STAT3/Survivin

¹ Department of Microbiology and Immunology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, the Walther Cancer Institute, Indianapolis, IN 46208
² Department of Internal Medicine and the Cancer Research and Science Center, Albuquerque, NM 87131

^* To whom correspondence should be addressed. E-mail: hbroxmey{at}iupui.edu.

	Abstract

Understanding survival/anti-apoptosis of murine embryonic stem (ES) cells may enhance their clinical potential. We hypothesized that Oct-4 might be involved in survival of undifferentiated ES cells under stress. Oct-4 tetracycline conditional knockout cell line ZHBtc4 was used to test this possibility and apoptosis was induced by either etoposide, heat shock or UV exposure. Apoptosis in Oct-4 knocked-down ES cells was significantly increased in response to all stress situations compared to parental cells. Oct-4 knock-down was not associated with changes in morphology, or expression of nanog, SSEA-1, KLF-4, or Sox2 within the time-frame and culture conditions used, suggesting that enhanced sensitivity of these cells to apoptosis was not due to an overtly differentiated state of the cells. To address potential intracellular mediators, we focused on IAP family member Survivin, an anti-apoptosis protein. The Survivin promoter was transfected into ES cells after knock-down of Oct-4. Survivin promoter activity was dramatically decreased in the Oct-4 knock-down cells. Western blots substantiated that Oct-4 knock-down ES cells had decreased Survivin protein expression. Since the Survivin promoter does not have binding sites for Oct-4, this suggested an indirect effect of Oct-4 on expression of Survivin. LIF-induced STAT3 is responsible for ES cell survival, and STAT3 regulates Survivin expression in breast cancer cells. Western Blot analysis showed that down regulated Oct-4 was associated with decreased phosphorylation of STAT3. Our results suggest that Oct-4 is essential for anti-apoptosis of ES cells in response to stress, effects that may be mediated through the STAT3/Survivin pathway.

This article has been cited by other articles:

				I.-M. Shih and K.-T. Kuo Power of the Eternal Youth: Nanog Expression in the Gestational Choriocarcinoma Am. J. Pathol., October 1, 2008; 173(4): 911 - 914. [Abstract] [Full Text] [PDF]