Ellis M J, Leav B A, Yang Z, Rasmussen A, Pearce A, Zweibel J A, Lippman M E, Cullen K J
Vincent T Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C, USA.
Mol Endocrinol. 1996 Mar;10(3):286-97. doi: 10.1210/mend.10.3.8833657.
We have investigated the autocrine regulation of insulin-like growth factor-II (IGF-II) signaling by the insulin-like growth factor-I receptor (IGF-IR) and the insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-IIR) in MCF-7 breast cancer cells, employing retroviruses encoding both IGF-I, IGF-II, and IGF-I and II mutants with reductions in affinity for either the IGF-IR or the IGF-IIR. These studies revealed reciprocal roles for IGF-IR and IGF-IIR affinity in the regulation of autocrine IGF-II activity. IGF-IR affinity was required for serum-free proliferation but also for efficient IGF-II secretion. In contrast, cellular proliferation, receptor tyrosine kinase-dependent signaling, and extracellular IGF-II protein accumulation were all reduced in the presence of IGF-IIR affinity. Inhibition of IGF-II signaling appeared to be the sole consequence of IGF-IIR affinity, as no cellular responses attributable to selective IGF-IIR binding by a reduced IGF-IR affinity IGF-II mutant could be detected. By operating as an IGF-II antagonist, the IGF-IIR has tumor suppressor-like properties, a suggestion consistent with reports of loss of heterozygosity at the IGF-IIR locus in a variety of human malignancies.
我们利用编码胰岛素样生长因子-I（IGF-I）、胰岛素样生长因子-II（IGF-II）以及对胰岛素样生长因子-I受体（IGF-IR）或胰岛素样生长因子-II/甘露糖6-磷酸受体（IGF-IIR）亲和力降低的IGF-I和IGF-II突变体的逆转录病毒，研究了MCF-7乳腺癌细胞中IGF-IR和IGF-IIR对胰岛素样生长因子-II（IGF-II）信号传导的自分泌调节。这些研究揭示了IGF-IR和IGF-IIR亲和力在自分泌IGF-II活性调节中的相互作用。无血清增殖需要IGF-IR亲和力，高效的IGF-II分泌也需要它。相反，在存在IGF-IIR亲和力的情况下，细胞增殖、受体酪氨酸激酶依赖性信号传导以及细胞外IGF-II蛋白积累均减少。IGF-II信号传导的抑制似乎是IGF-IIR亲和力的唯一结果，因为未检测到由亲和力降低的IGF-IR的IGF-II突变体与IGF-IIR选择性结合所引起的细胞反应。通过作为IGF-II拮抗剂发挥作用，IGF-IIR具有肿瘤抑制样特性，这一观点与多种人类恶性肿瘤中IGF-IIR基因座杂合性缺失的报道一致。
