Nahor Irit, Abramovitch Shirley, Engeland Kurt, Werner Haim
Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
Growth Horm IGF Res. 2005 Dec;15(6):388-96. doi: 10.1016/j.ghir.2005.07.005. Epub 2005 Sep 21.
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.
胰岛素样生长因子-I受体（IGF-IR）在恶性转化中起关键作用。与其抗凋亡作用一致，IGF-IR基因在包括结直肠肿瘤在内的大多数癌症类型中均过度表达。最近发现的p53同源物p63和p73具有一些p53的生物学特性，包括反式激活p53反应性基因和诱导凋亡的能力。在本研究中，我们检验了这样一个假说，即p63/p73蛋白可能通过涉及IGF-IR基因表达调控的机制促进结肠癌细胞增殖。通过在源自结肠癌的HCT116细胞中进行瞬时共表达分析，我们发现这两种蛋白均以剂量依赖的方式抑制IGF-IR启动子活性和内源性IGF-IR水平，而突变蛋白在抑制IGF-IR基因表达的能力上则显著受损。这些结果与以下观点相符，即结肠癌中p63/p73介导的信号转导通路的破坏可能导致IGF-IR基因转录增加。总之，我们已确定IGF-IR基因为p63/p73作用的一个新的下游靶点。
