Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1and results in apoptosis and tumor suppression (original) (raw)

Nature Medicine volume 4, pages 835–838 (1998)Cite this article

Abstract

Previously, we cloned a cDNA fragment, TSIP 2 (tumor suppressor inhibited pathway clone 2), that detects by northern blot analysis of M1-LTR6 cells a 3-kb mRNA downregulated during p53-induced apoptosis1. Cloning the full-length TSIP 2 cDNA showed that it corresponds to the presenilin 1 (PS1) gene, in which mutations have been reported in early-onset familial Alzheimer's disease2–4. Here we demonstrate that PS1is downregulated in a series of model systems for p53-dependent and p53-independent apoptosis and tumor suppression. To investigate the biological relevance of this downregulation, we stably transfected U937 cells with antisense PS1 cDNA. The downregulation of PS1 in these U937 transfectants results in reduced growth with an increased fraction of the cells in apoptosis. When injected into mice homozygous for severe combined immunodeficiency disease (scid/scid mice), these cells show a suppression of their malignant phenotype. Our results indicate that PS1, initially identified in a neurodegenerative disease, may also be involved in the regulation of cancer-related pathways.

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Author notes

  1. Véronique Alvaro and Sylvie Prieur: V.A. and S.P. contributed equally to this work
  2. Adam Telerman: Correspondence should be addressed to A.T.; email: Telerman@cephb.fr

Authors and Affiliations

  1. Fondation Jean Dausset-CEPH (Human Polymorphism Study Center), 27 rue Juliette Dodu, 75010, Paris, France
    Jean-Pierre Roperch, Véronique Alvaro, Sylvie Prieur, Mona Nemani, Florence Lethrosne, Laurence Piouffre, Jean Dausset, Robert Amson & Adam Telerman
  2. Department of Molecular Biology, Université Libre de Bruxelles, B-1640, Rhode-St-Genèse, Belgium
    Marcel Tuynder
  3. Flow Cytometry Unit, Institut Jacques Monod, 2 Place Jussieu, 75251, Paris, Cedex 05, France
    Marie-Claude Gendron
  4. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel
    David Israeli & Moshe Oren

Authors

  1. Jean-Pierre Roperch
  2. Véronique Alvaro
  3. Sylvie Prieur
  4. Marcel Tuynder
  5. Mona Nemani
  6. Florence Lethrosne
  7. Laurence Piouffre
  8. Marie-Claude Gendron
  9. David Israeli
  10. Jean Dausset
  11. Moshe Oren
  12. Robert Amson
  13. Adam Telerman

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Roperch, JP., Alvaro, V., Prieur, S. et al. Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1and results in apoptosis and tumor suppression.Nat Med 4, 835–838 (1998). https://doi.org/10.1038/nm0798-835

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