Tanaka E M, Drechsel D N, Brockes J P
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK.
Curr Biol. 1999;9(15):792-9. doi: 10.1016/s0960-9822(99)80362-5.
Adult urodele amphibians such as the newt have remarkable regenerative ability, and a critical aspect of this is the ability of differentiated cells to re-enter the cell cycle and lose their differentiated characteristics. Unlike mammalian myotubes, cultured newt myotubes are able to enter and traverse S phase, following serum stimulation, by a pathway leading to phosphorylation of the retinoblastoma protein. The extracellular regulation of this pathway is unknown.
Like their mammalian counterparts, newt myotubes were refractory to mitogenic growth factors such as the platelet-derived growth factor (PDGF), which act on their mononucleate precursor cells. Cultured newt myotubes were activated to enter S phase by purified thrombin in the presence of subthreshold amounts of serum. The activation proceeded by an indirect mechanism in which thrombin cleaved components in serum to generate a ligand that acted directly on the myotubes. The ligand was identified as a second activity present in preparations of crude thrombin and that was active after removal of all thrombin activity. It induced newt myotubes to enter S phase in serum-free medium, and it acted on myotubes but not on the mononucleate precursor cells. Cultured mouse myotubes were refractory to this indirect mechanism of S-phase re-entry.
These results provide a link between reversal of differentiation and the acute events of wound healing. The urodele myotube responds to a ligand generated downstream of thrombin activation and re-enters the cell cycle. Although this ligand can be generated in mammalian sera, the mammalian myotube is unresponsive. These results provide a model at the cellular level for the difference in regenerative ability between urodeles and mammals.
成年有尾两栖动物，如蝾螈，具有非凡的再生能力，其中一个关键方面是分化细胞重新进入细胞周期并丧失其分化特征的能力。与哺乳动物的肌管不同，培养的蝾螈肌管在血清刺激后能够通过导致视网膜母细胞瘤蛋白磷酸化的途径进入并穿越S期。该途径的细胞外调节尚不清楚。
与它们的哺乳动物对应物一样，蝾螈肌管对诸如血小板衍生生长因子（PDGF）等促有丝分裂生长因子不敏感，这些因子作用于它们的单核前体细胞。在亚阈值量血清存在下，纯化的凝血酶可激活培养的蝾螈肌管进入S期。激活通过间接机制进行，其中凝血酶切割血清中的成分以产生直接作用于肌管的配体。该配体被鉴定为粗凝血酶制剂中存在的第二种活性，并且在去除所有凝血酶活性后仍具有活性。它诱导蝾螈肌管在无血清培养基中进入S期，并且它作用于肌管而不作用于单核前体细胞。培养的小鼠肌管对这种S期重新进入的间接机制不敏感。
这些结果提供了分化逆转与伤口愈合急性事件之间的联系。有尾两栖动物肌管对凝血酶激活下游产生的配体作出反应并重新进入细胞周期。尽管这种配体可以在哺乳动物血清中产生，但哺乳动物肌管无反应。这些结果在细胞水平上为有尾两栖动物和哺乳动物再生能力的差异提供了一个模型。
