ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis

Abstract

DNA damage and/or hyperproliferative signals activate the wild-type p53 tumor suppressor protein, which induces a G₁ cell cycle arrest or apoptosis. Although the mechanism of p53-mediated cell cycle arrest is fairly well defined, the p53-dependent pathway regulating apoptosis is poorly understood. Here we report the functional characterization of murine ei24 (also known asPIG8), a gene directly regulated by p53, whose overexpression negatively controls cell growth and induces apoptotic cell death. Ectopic ei24 expression markedly inhibits cell colony formation, induces the morphological features of apoptosis, and reduces the number of β-galactosidase-marked cells, which is efficiently blocked by coexpression of Bcl-X_L. Theei24/PIG8 gene is localized on human chromosome 11q23, a region frequently altered in human cancers. These results suggest that ei24 may play an important role in negative cell growth control by functioning as an apoptotic effector of p53 tumor suppressor activities.

ACKNOWLEDGMENTS

We especially thank JinLing Wang and John R. Jeffers for their technical assistance and John L. Cleveland for critically reviewing the manuscript. We also acknowledge the contributions of Sam Lucas and Richard Ashmun to cell cycle analyses, of Linda Valentine and Thomas Look to the cytogenetic analyses, and of Richard Bram to the microinjection studies. We thank Richard Kriwacki for his advice on the predicted structure of ei24/PIG8.

This work was supported in part by NIH/NCI grant CA63230 (to G.P.Z.), NIH/NCI Cancer Center Support Grant 5 P30 CA21765, and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital (ALSAC).