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Telomerase Activation in Mouse Mammary Tumors: Lack of Detectable Telomere Shortening and Evidence for Regulation of Telomerase RNA with Cell Proliferation

Authors
Publisher
American Society for Microbiology
Publication Date
Keywords
  • Mammary Tumor Virus
  • Mouse
  • Telomere
  • Telomerase
Disciplines
  • Biology
  • Chemistry

Abstract

MOLECULAR AND CELLULAR BIOLOGY, July 1996, p. 3765-3172 0270-7306/96/$O4.00 + 0 Copyright 0 1996, American Society for Microbiology Vol. 16, No. 7 Telomerase Activation in Mouse Mammary Tumors: Lack of Detectable Telomere Shortening and Evidence for Regulation of Telomerase RNA with Cell Proliferation D. BROCCOLI,' L. A. GODLEY,2*3 L. A. DONEHOWER; H. E. VARMUS? AND T. DE LANGE'* Laboratory for Cell Biology and Genetics, The Rockefeller University, New Yo&, New Yo& 10021'; Division of Basic Science, National Cancer Institute, Bethesda, Maryland 20892'; Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 941433; and Division of Molecular Virology, Baylor College of Medicine, Houston, Twas 770304 Received 22 Janualy 1996/Returned for modification 20 March 1996iAccepted 3 April 1996 Activation of telomerase in human cancers is thought to be necessary to overcome the progressive loss of telomeric DNA that accompanies proliferation of normal somatic cells. According to this model, telomerase provides a growth advantage to cells in which extensive terminal sequence loss threatens viability. To test these ideas, we have examined telomere dynamics and telomerase activation during mammary tumorigenesis in mice carrying a mouse mammary tumor virus long terminal repeat-driven Wnt-I transgene. We also analyzed Wnt-I-induced mammary tumors in mice lacking p53 function. Normal mammary glands, hyperplastic mam- mary glands, and mammary carcinomas all had the long telomeres (20 to 50 kb) typical of Mus musculus and did not show telomere shortening during tumor development. Nevertheless, telomerase activity and the RNA component of the enzyme were consistently upregulated in Wnt-I -induced mammary tumors compared with normal and hyperplastic tissues. The upregulation of telomerase activity and RNA also occurred during tumorigenesis in p53-deficient mice. The expression of telomerase RNA correlated strongly with his

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