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.
Kurzik-Dumke
Ursula
U
Institute of Medical Microbiology and Hygiene, Comparative Tumor Biology Group, Faculty of Medicine, Johannes Gutenberg University, 55131 Mainz, Germany. kurzik@mail.uni-mainz.de
Hörner
Manuela
M
Czaja
Joachim
J
Nicotra
Maria Rita
MR
Simiantonaki
Nektaria
N
Koslowski
Michael
M
Natali
Pier Giorgio
PG
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000912:Antibodies, Neoplasm; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D017931:DNA Primers; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D012326:RNA Splicing; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D000912:Antibodies, Neoplasm; D017931:DNA Primers; C120664:DNAJA3 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins