Gastrin-regulated expression of p53 in transformed enterochromaffin-like cells in the African rodent mastomys

The tumor suppressor p53 functions at the G1/S-phase checkpoint of the cell cycle to direct cells that have accumulated somatic mutations toward apopt osis and away from mitosis. The p53 gene is commonly mutated in human cance rs, but the molecular mechanisms regulating this event are not clear. The A frican rodent mastomys exhibits a genetic predisposition to develop gastric carcinoids derived from enterochromaffin-like (ECL) cells. The ECL cell tr ansformation can be accelerated by acid inhibition-induced hypergastrinemia . This study evaluates the alteration of p53 during the rapid ECL cell tran sformation. Hypergastrinemia was generated by the irreversible histamine-2 receptor antagonist loxtidine for 8 weeks (hyperplasia) and 16 weeks (neopl asia). p53 expression was evaluated in fundic mucosa from different stages of transformation by Western blot analysis and immunohistochemistry using m onoclonal antibodies against wild-type p53. RT-PCR and molecular sequence a nalysis of p53 were undertaken with mRNA isolated from purified ECL cells. Overproduction of the wild type of p53 was evident in ECL cells during hype rgastrinemia, and the molecular characteristics of p53 were determined in n aive 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.