title: The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells.
abstract: The insulin-like growth factor-I receptor (IGF-IR) has a critical role in malignant transformation. Consistent with its antiapoptotic role, the IGF-IR gene is overexpressed in most types of cancer, including colorectal tumors. The recently identified p53 homologues, p63 and p73, exhibit some of the biological properties of p53, including the ability to transactivate p53-responsive genes and to induce apoptosis. In the present study, we examined the hypothesis that p63/p73 proteins may contribute to colon cancer cell proliferation via mechanism/s that involve regulation of IGF-IR gene expression. Using transient co-expression assays in colon cancer-derived HCT116 cells, we showed that both proteins inhibit IGF-IR promoter activity and endogenous IGF-IR levels in a dose-dependent manner, whereas mutant proteins are significantly impaired in their ability to suppress IGF-IR gene expression. These results are compatible with the notion that disruption of p63/p73-mediated signal transduction pathways in colon cancer may lead to increased IGF-IR gene transcription. In summary, we have identified the IGF-IR gene as a novel downstream target for p63/p73 action.
authors.affiliation: Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Nahor
authors.forename: Shirley
authors.initials: S
authors.lastname: Abramovitch
authors.forename: Kurt
authors.initials: K
authors.lastname: Engeland
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017526:Receptor, IGF Type 1; D001616:beta-Galactosidase