Barnard J A, Graves-Deal R, Pittelkow M R, DuBois R, Cook P, Ramsey G W, Bishop P R, Damstrup L, Coffey R J
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2576.
J Biol Chem. 1994 Sep 9;269(36):22817-22.
Several polypeptide growth factors related to epidermal growth factor (EGF) have been identified recently, including transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), heparin-binding EGF-like growth factor (HB-EGF), and betacellulin (BTC). These peptides all bind to the EGF receptor (EGFr). In an effort to understand redundancy within this peptide family and interactions among these related peptides, we compared the biological activities of EGF, TGF-alpha, AR, and HB-EGF in an EGF-responsive, nontransformed intestinal epithelial line (RIE-1) and also determined the effect of individual EGF-related peptides on the expression of related family members in these cells. TGF-alpha, AR, HB-EGF, and EGF were equipotent in stimulating [3H]thymidine incorporation by RIE-1 cells and bound the EGFr with equivalent affinity. Each EGF-related peptide induced the mRNA expression of the remaining family members, including BTC. HB-EGF and AR mRNAs were induced rapidly (within 30 min) and to a greater extent than TGF-alpha and BTC mRNAs, suggesting heterogeneity in the molecular mechanisms for induction. This same pattern was observed for all EGF-related peptides tested. A similar pattern of mRNA induction was observed in secondary cultures of human keratinocytes and in LIM1215 colon adenocarcinoma cells. Nuclear run-on analysis showed that induction of AR and HB-EGF is, at least in part, regulated at the level of gene transcription. Concurrent treatment with HB-EGF and cycloheximide resulted in superinduction of HB-EGF and AR, suggesting that these peptides are immediate early genes in RIE-1 cells. Our results demonstrate an equivalent biological response to EGF-related peptides in RIE-1 cells and further indicate that extensive auto-induction and cross-induction occur within the EGF-related peptide family in several EGF-responsive epithelial cell types.
最近已鉴定出几种与表皮生长因子（EGF）相关的多肽生长因子，包括转化生长因子-α（TGF-α）、双调蛋白（AR）、肝素结合表皮生长因子样生长因子（HB-EGF）和β细胞素（BTC）。这些肽均与EGF受体（EGFr）结合。为了了解该肽家族内的冗余性以及这些相关肽之间的相互作用，我们比较了EGF、TGF-α、AR和HB-EGF在对EGF有反应的非转化肠上皮细胞系（RIE-1）中的生物学活性，并确定了单个EGF相关肽对这些细胞中相关家族成员表达的影响。TGF-α、AR、HB-EGF和EGF在刺激RIE-1细胞掺入[3H]胸苷方面具有同等效力，并以同等亲和力与EGFr结合。每种EGF相关肽均诱导其余家族成员的mRNA表达，包括BTC。HB-EGF和AR的mRNA被快速诱导（30分钟内），且诱导程度大于TGF-α和BTC的mRNA，这表明诱导的分子机制存在异质性。在所测试的所有EGF相关肽中均观察到相同的模式。在人角质形成细胞的传代培养物和LIM1215结肠腺癌细胞中也观察到了类似的mRNA诱导模式。细胞核连续分析表明，AR和HB-EGF的诱导至少部分在基因转录水平受到调控。HB-EGF与环己酰亚胺同时处理导致HB-EGF和AR的超诱导，这表明这些肽是RIE-1细胞中的即刻早期基因。我们的结果证明了RIE-1细胞对EGF相关肽具有同等的生物学反应，并进一步表明在几种对EGF有反应的上皮细胞类型中，EGF相关肽家族内发生广泛的自诱导和交叉诱导。
