Luque E A, Tang L H, Bortecen K H, Kidd M, Miu K, Efstathiou J A, Modlin I M
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
J Clin Gastroenterol. 1998;27 Suppl 1:S116-24. doi: 10.1097/00004836-199800001-00019.
The tumor suppressor p53 functions at the G1/S-phase checkpoint of the cell cycle to direct cells that have accumulated somatic mutations toward apoptosis and away from mitosis. The p53 gene is commonly mutated in human cancers, but the molecular mechanisms regulating this event are not clear. The African rodent mastomys exhibits a genetic predisposition to develop gastric carcinoids derived from enterochromaffin-like (ECL) cells. The ECL cell transformation can be accelerated by acid inhibition-induced hypergastrinemia. This study evaluates the alteration of p53 during the rapid ECL cell transformation. Hypergastrinemia was generated by the irreversible histamine-2 receptor antagonist loxtidine for 8 weeks (hyperplasia) and 16 weeks (neoplasia). p53 expression was evaluated in fundic mucosa from different stages of transformation by Western blot analysis and immunohistochemistry using monoclonal antibodies against wild-type p53. RT-PCR and molecular sequence analysis of p53 were undertaken with mRNA isolated from purified ECL cells. Overproduction of the wild type of p53 was evident in ECL cells during hypergastrinemia, and the molecular characteristics of p53 were determined in naive and transformed ECL cells. p53 was mutated at the C-terminus in ECLoma induced by hypergastrinemia. Therefore, p53 is altered from overproduction to mutation during the development of hypergastrinemia-induced ECLoma and it may therefore play a role in the cell transformation.
肿瘤抑制因子p53在细胞周期的G1/S期检查点发挥作用，引导积累了体细胞突变的细胞走向凋亡，远离有丝分裂。p53基因在人类癌症中常发生突变，但其调控这一过程的分子机制尚不清楚。非洲啮齿动物马斯托鼠表现出从肠嗜铬样（ECL）细胞发生胃类癌的遗传易感性。酸抑制诱导的高胃泌素血症可加速ECL细胞转化。本研究评估了快速ECL细胞转化过程中p53的变化。通过不可逆的组胺-2受体拮抗剂洛替丁诱导高胃泌素血症8周（增生）和16周（肿瘤形成）。通过蛋白质印迹分析和使用抗野生型p53单克隆抗体的免疫组织化学，评估不同转化阶段胃底黏膜中p53的表达。对从纯化的ECL细胞中分离的mRNA进行p53的逆转录-聚合酶链反应（RT-PCR）和分子序列分析。高胃泌素血症期间，ECL细胞中野生型p53明显过量产生，并在未转化和转化的ECL细胞中确定了p53的分子特征。高胃泌素血症诱导的ECL瘤中，p53在C末端发生突变。因此, 在高胃泌素血症诱导的ECL瘤发生过程中，p53从过量产生转变为突变，因此它可能在细胞转化中发挥作用。
