Stable expression of temperature-sensitive p53: a suitable model to study wild-type p53 function in pancreatic carcinoma cells.
Pancreatic adenocarcinoma is an extremely aggressive malignancy with a dismal prognosis. Inactivation of the p53 tumor-suppressor gene occurs in approximately 50% of primary tumors and is thought to account for a failure of the tumor cells to undergo growth arrest and apoptosis in response to chemotherapy. Hence, it is of interest to study the consequences of the restoration of wild-type (wt) p53 function in pancreatic carcinoma cells. Therefore, we retrovirally transduced temperature-sensitive (ts) human p53 into the p53-null pancreatic carcinoma cell line AsPC-1. ts p53 has a mutant phenotype at 37.5 degrees C, and a wt conformation at 32.5 degrees C. Stable expression of p53 in wt conformation caused upregulation of the p53 responsive gene p21Waf1/Cip1, and G1 growth arrest, but failed to induce Bax expression or apoptosis. In addition, we examined the effect of wt p53 expression on DNA damaging treatment. Interestingly, the doxorubicin- and radiation-induced S-/G2-phase arrests were suppressed by p53 in wt conformation. These results demonstrate that the ts p53/AsPC-1 model is suitable to investigate the effect of wt p53 restoration in pancreatic carcinoma cells.
Nuevemann
Dieter
D
Department of General and Thoracic Surgery, Research Unit Molecular Oncology, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Christgen
Matthias
M
Ungefroren
Hendrik
H
Kalthoff
Holger
H
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D013696:Temperature; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53