DuBois R N, Awad J, Morrow J, Roberts L J, Bishop P R
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
J Clin Invest. 1994 Feb;93(2):493-8. doi: 10.1172/JCI116998.
Growth factors and tumor promoters have been shown to play a role in intestinal epithelial growth regulation and transformation. In this study, transforming growth factor-alpha (TGF alpha) and the tumor promoter, tetradecanoyl phorbol acetate (TPA), are shown to stimulate the production of eicosanoids by rat intestinal epithelial (RIE-1) cells in culture. A 4.5-kb mRNA, which hybridizes to the mouse cyclooxygenase-2 cDNA probe, is elevated 18-fold within 30 min after TGF alpha or TPA treatment. Stimulation of RIE-1 cells with TGF alpha leads to the increase of a protein (M(r) approximately 69,000), which binds a monospecific antibody to the mouse cyclooxygenase-2 protein. Dexamethasone markedly inhibits the increase of the 4.5-kb mRNA. Pretreatment of TGF alpha or TPA-stimulated RIE-1 cells with dexamethasone or cyclooxygenase inhibitors prevents the increase in eicosanoid production by these cells. Treatment of quiescent RIE-1 cells with TGF alpha stimulates mitogenesis. This mitogenic activity is blocked by pretreating the cells with dexamethasone or cyclooxygenase inhibitors. A mitogen-inducible cyclooxygenase gene is thus shown to be regulated by TGF alpha and TPA in rat intestinal epithelial cells. We suggest that products of an intestinal growth factor-inducible cyclooxygenase may play a role in the regulation of mitogenesis.
生长因子和肿瘤促进剂已被证明在肠道上皮生长调节和转化中发挥作用。在本研究中，转化生长因子-α（TGFα）和肿瘤促进剂十四酰佛波醇乙酸酯（TPA）被证明可刺激培养的大鼠肠道上皮（RIE-1）细胞产生类花生酸。一种与小鼠环氧化酶-2 cDNA探针杂交的4.5 kb mRNA，在TGFα或TPA处理后30分钟内升高了18倍。用TGFα刺激RIE-1细胞会导致一种蛋白质（分子量约为69,000）增加，该蛋白质与针对小鼠环氧化酶-2蛋白的单特异性抗体结合。地塞米松显著抑制4.5 kb mRNA的增加。用地塞米松或环氧化酶抑制剂预处理TGFα或TPA刺激的RIE-1细胞可防止这些细胞类花生酸产生的增加。用TGFα处理静止的RIE-1细胞可刺激有丝分裂。这种有丝分裂活性可通过用地塞米松或环氧化酶抑制剂预处理细胞来阻断。因此，在大鼠肠道上皮细胞中，一种有丝分裂原诱导的环氧化酶基因被证明受TGFα和TPA调控。我们认为肠道生长因子诱导的环氧化酶产物可能在有丝分裂调节中发挥作用。
