Yan Chunhong, Boyd Douglas D
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cell Cycle. 2006 May;5(9):926-9. doi: 10.4161/cc.5.9.2714. Epub 2006 May 1.
ATF3 is a member of the ATF/CREB family of transcription factors involved in the cellular response to a large variety of stresses including DNA damage. However, neither the signaling leading to nor the biological significance of its induction upon stress is well understood. Although it is generally believed that ATF3 exerts its function in the stress response by regulating transcription, to date, only a limited number of target genes have been identified. We recently reported that ATF3 interacts with the tumor suppressor p53 to increase its stability in the genotoxic response. While providing the cell a general means of responding to diverse adverse environment cues, this mechanism confers ATF3 with an ability to promote tumor suppressor functions. Conversely, dysfunction of ATF3 impairs the p53-mediated cellular response to DNA damage, allowing cells to be readily transformed by oncogenes. Consistent with this notion is the observation of downregulated ATF3 expression in most human cancers. Therefore, our findings indicate that ATF3 intersects with p53-associated pathways ensuring genomic integrity. The ability of ATF3 to stabilize p53-induced pathways thus represents a means of effectively countering DNA damage caused by environmental insult the latter leading to oncogene activation and ultimately malignant transformation.
ATF3是ATF/CREB转录因子家族的成员，参与细胞对包括DNA损伤在内的多种应激的反应。然而，导致其在应激时被诱导的信号传导以及这种诱导的生物学意义都尚未得到很好的理解。尽管人们普遍认为ATF3通过调节转录在应激反应中发挥作用，但迄今为止，仅鉴定出有限数量的靶基因。我们最近报道，ATF3与肿瘤抑制因子p53相互作用，以增加其在基因毒性反应中的稳定性。在为细胞提供一种应对各种不利环境信号的通用方式的同时，这种机制赋予了ATF3促进肿瘤抑制功能的能力。相反，ATF3功能障碍会损害p53介导的细胞对DNA损伤的反应，使细胞容易被癌基因转化。与这一观点一致的是，在大多数人类癌症中观察到ATF3表达下调。因此，我们的研究结果表明，ATF3与p53相关途径相交，确保基因组完整性。ATF3稳定p53诱导途径的能力因此代表了一种有效对抗由环境损伤引起的DNA损伤的方式，后者导致癌基因激活并最终发生恶性转化。
