Trefoil factor 1 (TFF1/pS2) deficiency activates the unfolded protein response.
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.


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.


CONCLUSIONS
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.
D000818:Animals; D018076:DNA, Complementary / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism*; D006133:Growth Substances / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000648:ultrastructure; D010455:Peptides / Q000172:deficiency* / Q000378:metabolism; D017510:Protein Folding; D011506:Proteins; D011706:Pyloric Antrum / Q000378:metabolism / Q000648:ultrastructure; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D018076:DNA, Complementary; D000091342:Endoplasmic Reticulum Chaperone BiP; D006133:Growth Substances; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010455:Peptides; D011506:Proteins; C051838:TFF1 protein, human; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins