Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor.

Recently, we identified htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs [l(2)tid], as a direct molecular ligand of the adenomatous polyposis coli (APC) tumor suppressor. The gene encodes three cytosolic (Tid50, Tid48 and Tid46) and three mitochondrial (Tid43, Tid40 and Tid38) proteins. In the colorectal epithelium the cytosolic forms hTid50/hTid48 interact under physiological conditions with the N-terminal region of APC. This complex which associates with additional proteins such as Hsp70, Hsc70, Actin, Dvl and Axin defines a novel physiological state of APC unrelated to beta-catenin degradation. Here we show that the expression of the genes htid-1 and APC was altered in colorectal tumors. These changes concerned both the localization and the expression level of all three htid-1 splice variants and of APC. Furthermore, we showed that the protein products of the two tumor suppressors co-localized in the basal and apical region of normal colon epithelia and that loss of differentiation capacity of colorectal cancers correlated with a shift in their expression patterns from compartmentalized to diffuse cytoplasmic. These findings support our hypothesis that the building of the multi-component complex mentioned above is associated with the maintenance of the polarity of cells and tissues. In addition, we provide evidence that colon cancer progression correlates with up-regulation of htid-1 and its ligand Hsp70. Since the Tid proteins are members of the DnaJ-like protein family, an essential component of the Hsp70/Hsc70 chaperone machinery, our findings describe a novel, causal link between the function of chaperone machines, APC-mediated Wg/Wnt signaling and tumor development.

Htid-1, the human homolog of the Drosophila melanogaster l(2)tid tumor suppressor, defines a novel physiological role of APC.

Htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs (l(2)tid) encodes three splice forms translated into three cytosolic - Tid50, Tid48 and Tid46 - and three mitochondrial - Tid43, Tid40 and Tid38 - proteins. Here we provide evidence for the association of the endogenous Tid50/Tid48 proteins with the adenomatous polyposis coli (APC) tumor suppressor in normal colon epithelium, colorectal cancer cells and mouse NIH3T3 fibroblasts. Using the Glutathione S-transferase binding assay we show that the N-terminal region including the Armadillo domain (ARM) of APC is sufficient to bind the Tid molecules. Using immunoprecipitation and confocal microscopy we show that the two molecular partners complex at defined areas of the cells with further proteins such as Hsp70, Hsc70, Actin, Dvl and Axin. Our data implicate that the formation of the complex is not associated with APC's involvement in beta-Catenin degradation. Furthermore, though it is linked to Actin it is neither associated with regulation of Actin cytoskeleton due to APC's binding to Asef nor to Tid's binding to Ras-GAP. We suggest that the novel complex acts in maintaining APC's availability for its distinct roles in the Wnt signaling important for the cell to take the right decision, either to switch the cascade OFF or ON, thus, to regulate the onset of proliferation of the cells.