TY - JOUR
T1 - TreFoil factor 1 (TFF1/pS2) deficiency activates the unfolded protein response
AU - Torres, Luis Fernando
AU - Karam, Sherif M.
AU - Wendling, Corinne
AU - Chenard, Marie Pierre
AU - Kershenobich, David
AU - Tomasetto, Catherine
AU - Rio, Marie Christine
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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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U2 - 10.1007/bf03402153
DO - 10.1007/bf03402153
M3 - Article
C2 - 12359958
AN - SCOPUS:0036389657
SN - 1076-1551
VL - 8
SP - 273
EP - 282
JO - Molecular Medicine
JF - Molecular Medicine
IS - 5
ER -