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 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.
Luque
E A
EA
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
Tang
L H
LH
Bortecen
K H
KH
Kidd
M
M
Miu
K
K
Efstathiou
J A
JA
Modlin
I M
IM
D000595:Amino Acid Sequence; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000737:chemistry; D019861:Enterochromaffin-like Cells / Q000378:metabolism* / Q000473:pathology; D005755:Gastrins / Q000097:blood / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D006635:Histamine H2 Antagonists; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009115:Muridae; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D014230:Triazoles; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics
D017931:DNA Primers; D004273:DNA, Neoplasm; D005755:Gastrins; D006635:Histamine H2 Antagonists; D012333:RNA, Messenger; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C039993:loxtidine