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TreFoil Factor 1 (TFF1/pS2) Deficiency Activates the Unfolded Protein Response

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Abstract

Background

The trefoil factor 1 (TFF1/pS2) is a secreted gastrointestinal peptide that is often altered or lost in human gastric cancers. Consistently, mouse TFF1 deficiency leads to antropyloric tumors.

Materials and Methods

To investigate the gene expression alterations in response to the lack of TFF1, we performed differential expression analyses of TFF1 null antropyloric tumors using an array containing 588 cDNAs.

Results

Using total and enriched probes, 22 genes were found to be up-regulated. The identification of the genes for endoplasmic reticulum (ER)-resident GRP78, ERp72, and p58IPK proteins connected TFF1 deficiency to the unfolded protein response (UPR). Accordingly, CHOP10, a transcription factor induced early in response to ER stress, and the pleiotropic Clusterin, involved in protein folding, were also overexpressed. Northern blot analyses of 8 weeks and 1 year TFF1 null tumors confirmed that GRP78, ERp72, p58IPK, CHOP10, and Clusterin overexpression is a common and permanent feature shared by all TFF1 null antropyloric tumors. Finally, consistent with UPR, ultrastructural analyses showed that tumor rough ER was enlarged and contained dense material, supporting the hypothesis that TFF1 deficiency leads to the accumulation of misfolded proteins in the ER.

Conclusion

Together, our data provide the first evidence of a relationship between a member of the TFF family and the ER machinery. Whereas to date TFF1 is believed to act as an extracellular molecule, our results suggest a possible additional function for TFF1 in protein folding and/or secretion.

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Acknowledgments

We thank F. Ruffenach, I. Colas, and E. Troesch for their technical assistance, and C. Nourse for critical reading of the manuscript. L.F.T. was a recipient of a fellowship from the Instituto Nacional de Ciencias Médicas y de la Nutricion “Salvador Zubiran” (INCMNSZ), the Instituto de Investigaciones Biomédicas, UNAM, and the Consejo Nacional de Ciencia y Tecnologia (CONACYT). This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, the Ligue Nationale Française contre le Cancer and the Comités du Haut-Rhin et du Bas-Rhin and the Fondation de France.

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Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), BP 10142, 67404, Illkirch Cedex, C.U. de Strasbourg, France

    Corinne Wendling, Marie-Pierre Chenard, Catherine Tomasetto & Marie-Christine Rio

  2. Gastroenterology Department, Instituto Nacional de Ciencias Médicas y de la Nutricion “Salvador Zubiran” (INCMNSZ), Distrito Federal México, México

    Luis-Fernando Torres & David Kershenobich

  3. Department of Anatomy, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

    Sherif M. Karam

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  1. Luis-Fernando Torres
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Correspondence to Marie-Christine Rio.

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Torres, LF., Karam, S.M., Wendling, C. et al. TreFoil Factor 1 (TFF1/pS2) Deficiency Activates the Unfolded Protein Response. Mol Med 8, 273–282 (2002). https://doi.org/10.1007/BF03402153

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