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J. Biol. Chem., Vol. 280, Issue 24, 22776-22787, June 17, 2005

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Human Telomerase Reverse Transcriptase Immortalizes Bovine Lens Epithelial Cells and Suppresses Differentiation through Regulation of the ERK Signaling Pathway^*

Juan Wang¶, Hao Feng||, Xiao-Qin Huang||, Hua Xiang**, Ying-Wei Mao, Jin-Ping Liu, Qin Yan||, Wen-Bin Liu||, Yan Liu||, Mi Deng||, Lili Gong||, Shuming Sun||, Chen Luo||, Shao-Jun Liu||, Xuan-Jie Zhang||, Yun Liu||, and David Wan-Cheng Li||¶¶

From the ^||College of Life Sciences, Hunan Normal University, Changsha, Hunan, China 410081, Department of Molecular Biology, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084, and Hormel Institute, University of Minnesota, Austin, Minnesota 55912

Telomerase is a specialized reverse transcriptase that extends telomeres of eukaryotic chromosomes. The functional telomerase complex contains a telomerase reverse transcriptase catalytic subunit and a telomerase template RNA. We have previously demonstrated that human telomerase reverse transcriptase (hTERT) catalytic subunit is functionally compatible with a telomerase template RNA from rabbit. In this study, we show that hTERT is also functionally compatible with a telomerase template RNA from bovine. Introduction of hTERT into bovine lens epithelial cells (BLECs) provides the transfected cells telomerase activity. The expressed hTERT in BLECs supports normal growth of the transfected cells for 108 population doublings so far, and these cells are still extremely healthy in both morphology and growth. In contrast, the vector-transfected cells display growth crisis after 20 population doublings. These cells run into cellular senescence due to shortening of the telomeres and also commit differentiation as indicated by the accumulation of the differentiation markers, -crystallin and filensin. hTERT prevents the occurrence of both events. By synthesizing new telomere, hTERT prevents replicative senescence, and through regulation of MEK/ERK, protein kinase C, and protein kinase A and eventual suppression of the MEK/ERK signaling pathway, hTERT inhibits differentiation of BLECs. Our finding that hTERT can suppress RAS/RAF/MEK/ERK signaling pathway to prevent differentiation provides a novel mechanism to explain how hTERT regulates cell differentiation.

Received for publication, January 3, 2005 , and in revised form, March 24, 2005.

^* This work was supported in part by the NEI, National Institutes of Health Grant EY15765, the Hormel Foundation, the Lotus Scholar Program Funds from the Ministry of Hunan Province Government, and Hunan Normal University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors have equally contributed to this work.

^¶ Present address: Division of Endocrinology, Diabetes, and Metabolism, Depts. of Medicine and Genetics and The Penn Diabetes Center, University of Pennsylvania, Philadelphia, PA 19104.

^** Present address: State Key Laboratory of Microbial Resources and Center for Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China.

Present address: Dept. of Pharmacology, University of Michigan, Ann Arbor, MI 48109.

^¶¶ To whom correspondence should be addressed: The Hormel Institute, University of Minnesota, 801 16th Ave., N. E., Austin, MN 55912. Tel.: 507-437-9636; Fax: 507-437-9606; E-mail: dwcli{at}hi.umn.edu.

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