TAp73 knockout shows genomic instability with infertility and tumor suppressor functions

  1. Richard Tomasini1,2,12,
  2. Katsuya Tsuchihara1,3,12,
  3. Margareta Wilhelm1,
  4. Masashi Fujitani4,
  5. Alessandro Rufini1,5,
  6. Carol C. Cheung1,6,
  7. Fatima Khan7,
  8. Annick Itie-Youten1,
  9. Andrew Wakeham1,
  10. Ming-sound Tsao8,
  11. Juan L. Iovanna2,
  12. Jeremy Squire9,
  13. Igor Jurisica10,
  14. David Kaplan4,
  15. Gerry Melino5,11,
  16. Andrea Jurisicova7, and
  17. Tak W. Mak1,13
  1. 1 The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, Ontario M5G 2C1, Canada;
  2. 2 Institut National de la Santé et de la Recherche Médicale Unité 624, Stress Cellulaire, 13288 Marseille Cedex 9, France;
  3. 3 Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan;
  4. 4 The Hospital for Sick Children MaRs Centre, Toronto Medical Discovery Tower, Toronto, Ontario M5G 1L7, Canada;
  5. 5 Biochemistry IDI-IRCCS Laboratory, c/o University of Rome “Tor Vergata,” 00133 Rome, Italy;
  6. 6 Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario M5G 2C4, Canada;
  7. 7 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario M5G 2C1, Canada;
  8. 8 Division of Applied Molecular Oncology, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada;
  9. 9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada;
  10. 10 Division of Signaling Biology, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada;
  11. 11 Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Leicester LE1 9HN, United Kingdom
  1. 12

    12 These authors contributed equally to this work.

Abstract

The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and ΔNp73, with opposing pro- and anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles of p73 isoforms in cellular events such as tumor initiation, embryonic development, and cell death remain unclear. To determine which aspects of p73 function are attributable to the TAp73 isoforms, we generated and characterized mice in which exons encoding the TAp73 isoforms were specifically deleted to create a TAp73-deficient (TAp73−/−) mouse. Here we show that mice specifically lacking in TAp73 isoforms develop a phenotype intermediate between the phenotypes of Trp73−/− and Trp53−/− mice with respect to incidence of spontaneous and carcinogen-induced tumors, infertility, and aging, as well as hippocampal dysgenesis. In addition, cells from TAp73−/− mice exhibit genomic instability associated with enhanced aneuploidy, which may account for the increased incidence of spontaneous tumors observed in these mutants. Hence, TAp73 isoforms exert tumor-suppressive functions and indicate an emerging role for Trp73 in the maintenance of genomic stability.

Keywords

Footnotes

  • 13

    13 Corresponding author.

    13 E-MAIL tmak{at}uhnres.utoronto.ca; FAX (416) 204 5300.

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1695308.

    • Received May 13, 2008.
    • Accepted August 6, 2008.
  • Freely available online through the Genes & Development Open Access option.

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