Inhibitory effect of Bcl-2 on p53-mediated transactivation following genotoxic stress

• Published in: Oncogene Vol. 18; no. 2; pp. 297 - 304
• Main Authors: ZHAN, Q, KONTNY, U, IGLESIAS, M, ALAMO, I. JR, YU, K, HOLLANDER, M. C, WOODWORTH, C. D, FORNACE, A. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 14.01.1999
• Subjects: Ageing, cell death; Apoptosis; Biological and medical sciences; Cell physiology; DNA Damage; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Humans; Methyl Methanesulfonate - pharmacology; Molecular and cellular biology; Mutagens - pharmacology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transcriptional Activation; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - metabolism; Human; Transcription; Induction; p53 Protein; Gene expression; Mutagen; Ionizing irradiation; Regulation(control); Cell line; Ultraviolet irradiation; Cell cycle; Tumor suppressor gene; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202310

In the cellular response to genotoxic stress, cell cycle checkpoint and apoptosis are considered to be two of the major biological events in maintaining genomic stability. The tumor suppressor p53 has been shown to play critical roles in these stress-induced cellular responses at least in part through the activation of its down-stream genes, such as p21CIP1/WAF1, GADD45 and BAX. In addition, p53 has been found to down-regulate the expression of BCL-2, which is able to block apoptosis induced by both p53-dependent and independent signaling events. In this report, we have found that increased expression of Bcl-2 protein in the human Burkitt's lymphoma WMN cell line suppressed apoptosis induced by different DNA-damaging agents. The induction of p53-regulated genes including GADD45, p21CIP1/WAF1 and BAX by genotoxic stress was substantially reduced in cells expressing high levels of Bcl-2 protein. Furthermore, Bcl-2 protein was shown to specifically suppress the p53-mediated transactivation of p21CIP1/WAF1 and PG13-CAT, which is a typical p53-binding-site reporter construct. Similarly, the inhibitory effect of Bcl-2 protein was seen in a GADD45 promoter reporter construct after treatment with methylmethane sulfonate or UV-radiation. These results indicate that in addition to its apoptosis-suppressing activity, Bcl-2 protein is able to inhibit transactivation of p53-regulated genes, which function in multiple important cellular responses to genotoxic stress, including the control of cell cycle checkpoints, cell growth suppression and DNA repair.