This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nishi, H.
Right arrow Articles by Isaka, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nishi, H.
Right arrow Articles by Isaka, K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2004, p. 6076-6083, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.6076-6083.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factor 1 Mediates Upregulation of Telomerase (hTERT)

Hirotaka Nishi,1* Toshihide Nakada,1 Satoru Kyo,2 Masaki Inoue,2 Jerry W. Shay,3 and Keiichi Isaka1

Department of Obstetrics and Gynecology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023,1 Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8641, Japan,2 The University of Texas Southwestern Medical Center at Dallas, Department of Cell Biology, Dallas, Texas 753093

Received 17 November 2003/ Returned for modification 10 December 2003/ Accepted 5 April 2004

Hypoxia occurs during the development of the placenta in the first trimester and correlates with both trophoblast differentiation and the induction of telomerase activity through hTERT expression. We sought to determine the mechanism of regulation of hTERT expression during hypoxia. We show that hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) and hTERT expression in the human placenta decrease with gestational age and that these are overexpressed in preeclamptic placenta, a major complication of pregnancy. Hypoxia not only transactivates the hTERT promoter activity but also enhances endogenous hTERT expression. The hTERT promoter region between –165 and +51 contains two HIF-1 consensus motifs, and in vitro reporter assays show that these are essential for hTERT transactivation by HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT expression during hypoxia, indicating that upregulation of hTERT by hypoxia is directly mediated through HIF-1. Our results provide persuasive evidence that the regulation of hTERT promoter activity by HIF-1 represents a mechanism for trophoblast growth during hypoxia and suggests that this may be a generalized response to hypoxia in various human disorders including resistance to cancer therapeutics by upregulating telomerase.

* Corresponding author. Mailing address: Department of Obstetrics and Gynecology, Tokyo Medical University, 6-7-1 Nishishinjuku Shinjuku-ku, Tokyo 160-0023, Japan. Phone: 81 3 3342 6111, ext. 5869. Fax: 81 3 3348 5918. E-mail: nishih{at}tokyo-med.ac.jp.

Molecular and Cellular Biology, July 2004, p. 6076-6083, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.6076-6083.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sullivan, R., Pare, G. C., Frederiksen, L. J., Semenza, G. L., Graham, C. H. (2008). Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Molecular Cancer Therapeutics 7: 1961-1973 [Abstract] [Full Text]  
  • Bell, E. L., Klimova, T. A., Eisenbart, J., Schumacker, P. T., Chandel, N. S. (2007). Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia. Mol. Cell. Biol. 27: 5737-5745 [Abstract] [Full Text]  
  • Lou, F., Chen, X., Jalink, M., Zhu, Q., Ge, N., Zhao, S., Fang, X., Fan, Y., Bjorkholm, M., Liu, Z., Xu, D. (2007). The Opposing Effect of Hypoxia-Inducible Factor-2{alpha} on Expression of Telomerase Reverse Transcriptase. Mol Cancer Res 5: 793-800 [Abstract] [Full Text]  
  • Rajakumar, A., Jeyabalan, A., Markovic, N., Ness, R., Gilmour, C., Conrad, K. P. (2007). Placental HIF-1{alpha}, HIF-2{alpha}, membrane and soluble VEGF receptor-1 proteins are not increased in normotensive pregnancies complicated by late-onset intrauterine growth restriction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R766-R774 [Abstract] [Full Text]  
  • Parmar, K., Mauch, P., Vergilio, J.-A., Sackstein, R., Down, J. D. (2007). Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc. Natl. Acad. Sci. USA 104: 5431-5436 [Abstract] [Full Text]  
  • Renaud, S., Loukinov, D., Abdullaev, Z., Guilleret, I., Bosman, F. T., Lobanenkov, V., Benhattar, J. (2007). Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res 35: 1245-1256 [Abstract] [Full Text]  
  • Lopez-Lazaro, M. (2006). Hypoxia-Inducible Factor 1 as a Possible Target for Cancer Chemoprevention. Cancer Epidemiol. Biomarkers Prev. 15: 2332-2335 [Abstract] [Full Text]  
  • Shieh, G.-S., Shiau, A.-L., Yo, Y.-T., Lin, P.-R., Chang, C.-C., Tzai, T.-S., Wu, C.-L. (2006). Low-Dose Etoposide Enhances Telomerase-Dependent Adenovirus-Mediated Cytosine Deaminase Gene Therapy through Augmentation of Adenoviral Infection and Transgene Expression in a Syngeneic Bladder Tumor Model.. Cancer Res. 66: 9957-9966 [Abstract] [Full Text]  
  • Chang, C.-C., Lin, M.-T., Lin, B.-R., Jeng, Y.-M., Chen, S.-T., Chu, C.-Y., Chen, R. J., Chang, K.-J., Yang, P.-C., Kuo, M.-L. (2006). Effect of connective tissue growth factor on hypoxia-inducible factor 1alpha degradation and tumor angiogenesis.. JNCI J Natl Cancer Inst 98: 984-995 [Abstract] [Full Text]  
  • Jagadeesh, S., Kyo, S., Banerjee, P. P. (2006). Genistein Represses Telomerase Activity via Both Transcriptional and Posttranslational Mechanisms in Human Prostate Cancer Cells. Cancer Res. 66: 2107-2115 [Abstract] [Full Text]  
  • Renaud, S., Loukinov, D., Bosman, F. T., Lobanenkov, V., Benhattar, J. (2005). CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res 33: 6850-6860 [Abstract] [Full Text]  
  • Wenger, R. H., Stiehl, D. P., Camenisch, G. (2005). Integration of Oxygen Signaling at the Consensus HRE. Sci Signal 2005: re12-re12 [Abstract] [Full Text]  
  • Pascale, E., Reale, G. C., D'Ambrosio, E. (2004). Tumor Cells Fail to trans-Induce Telomerase in Human Umbilical Vein Endothelial Cell Cultures. Cancer Res. 64: 7702-7705 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»