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Published 28 May 2002. doi:10.1083/jcb200108056
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© The Rockefeller University Press, 0021-9525/2002/5/761 $5.00
The Journal of Cell Biology, Volume 157, Number 5, May 28, 2002 761-770

Article

 The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis

Carine Bossenmeyer-Pourié1, Rama Kannan1, Stéphane Ribieras1, Corinne Wendling1, Isabelle Stoll1, Lars Thim2, Catherine Tomasetto1 and Marie-Christine Rio1

1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, 67404 Illkirch Cedex, C.U. de Strasbourg, France
2 Novo Nordisk, Novo Allé, DK-2880, Bagsvaerd, Denmark

Address correspondence to Marie-Christine Rio, IGBMC, BP 163, Illkirch Cedex, 67404, France. Tel.: 33-3-88-65-34-34. Fax: 33-3-88-65-32-01. E-mail: rio{at}igbmc.u-strasbg.fr

Trefoil factor (TFF)1 is synthesized and secreted by the normal stomach mucosa and by the gastrointestinal cells of injured tissues. The link between mouse TFF1 inactivation and the fully penetrant antropyloric tumor phenotype prompted the classification of TFF1 as a gastric tumor suppressor gene. Accordingly, altered expression, deletion, and/or mutations of the TFF1 gene are frequently observed in human gastric carcinomas. The present study was undertaken to address the nature of the cellular and molecular mechanisms targeted by TFF1 signalling. TFF1 effects were investigated in IEC18, HCT116, and AGS gastrointestinal cells treated with recombinant human TFF1, and in stably transfected HCT116 cells synthesizing constitutive or doxycycline-induced human TFF1. We observed that TFF1 triggers two types of cellular responses. On one hand, TFF1 lowers cell proliferation by delaying G1-S cell phase transition. This results from a TFF1-mediated increase in the levels of cyclin-dependent kinase inhibitors of both the INK4 and CIP subfamilies, leading to lower E2F transcriptional activity. On the other hand, TFF1 protects cells from chemical-, anchorage-free–, or Bad-induced apoptosis. In this process, TFF1 signalling targets the active form of caspase-9. Together, these results provide the first evidence of a dual antiproliferative and antiapoptotic role for TFF1. Similar paradoxical functions have been reported for tumor suppressor genes involved in cell differentiation, a function consistent with TFF1.

Key Words: trefoil factor 1; pS2; cell cycle; gastrointestinal differentiation; apoptosis


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