Lee M K, Zhao J, Smith S M, Tefft J D, Bringas P, Hwang C, Warburton D
Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles 90027, USA.
Pediatr Res. 1998 Dec;44(6):850-9. doi: 10.1203/00006450-199812000-00005.
Many of the signaling pathways regulating fetal lung mesenchymal cell proliferation are mediated by the Shc intracellular signaling proteins. Shc is expressed as three isoforms: 52 kD and 46 kD proteins (Shc 52 and Shc 46, respectively) translated from the same mRNA, and a 66 kD form (Shc 66) translated from a separate mRNA. Shc 52 is an activator of Ras and mitogen-activated protein kinase, whereas Shc 66 antagonizes Ras activation. The function of Shc 46 is unclear. We hypothesized that the Shc isoforms are differentially regulated during fetal mouse lung morphogenesis. Relative Shc 66 and Shc 46 protein expression are high until parturition (term = 18.5 d), when a dramatic decrease begins; by postconceptual d 20, relative Shc 66 and Shc 46 expression have fallen by 75 and 69%, respectively. A similar pattern of decreasing Shc 66 mRNA expression in the peripartum period was detected by reverse transcription and competitive polymerase chain reaction during the same period. By isoform-specific immunohistochemistry, Shc 66 is widely distributed in the embryonic lung but becomes restricted to the bronchial smooth muscle and overlying epithelia, periarterial smooth muscle, and the interlobar pleura late in gestation. After parturition, Shc 66 is virtually absent from the lung. All three Shc isoforms are phosphorylated by epidermal growth factor stimulation in fetal lung mesenchymal cells, indicating that Shc 66 is functional in these cells. These data indicate that Shc isoforms are differentially regulated during lung development.
许多调节胎儿肺间充质细胞增殖的信号通路是由Shc细胞内信号蛋白介导的。Shc以三种异构体形式表达：由同一mRNA翻译而来的52 kD和46 kD蛋白（分别为Shc 52和Shc 46），以及由单独的mRNA翻译而来的66 kD形式（Shc 66）。Shc 52是Ras和丝裂原活化蛋白激酶的激活剂，而Shc 66则拮抗Ras激活。Shc 46的功能尚不清楚。我们推测，在小鼠胎儿肺形态发生过程中，Shc异构体受到不同的调节。直到分娩时（足月为18.5天），Shc 66和Shc 46的相对蛋白表达一直很高，之后开始急剧下降；到妊娠后第20天，Shc 66和Shc 46的相对表达分别下降了75%和69%。在同一时期，通过逆转录和竞争性聚合酶链反应检测到围产期Shc 66 mRNA表达也有类似的下降模式。通过异构体特异性免疫组织化学方法发现，Shc 66在胚胎肺中广泛分布，但在妊娠后期局限于支气管平滑肌和覆盖的上皮、动脉周围平滑肌以及叶间胸膜。分娩后，肺中几乎不存在Shc 66。在胎儿肺间充质细胞中，所有三种Shc异构体都可被表皮生长因子刺激磷酸化，这表明Shc 66在这些细胞中具有功能。这些数据表明，在肺发育过程中，Shc异构体受到不同的调节。
