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Cell Cycle, Cell Death, and Senescence

Interaction and Functional Cooperation of the Cancer-Amplified Transcriptional Coactivator Activating Signal Cointegrator-2 and E2F-1 in Cell Proliferation¹

¹ Laboratory of Molecular Growth Regulation, National Institute of Health, Bethesda, MD;
² Department of Molecular Biology, Pusan National University, Busan, Republic of Korea;
³ Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, Republic of Korea;
⁴ Department of Biology, Kyungpook National University, DaeGu, Republic of Korea; and
⁵ Department of Medicine/Endocrinology, Baylor College of Medicine Houston, TX

Requests for reprints: JaeHun Cheong, Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea. Phone: 82-51-510-2277; Fax: 82-51-513-9258. E-mail: molecule85{at}pusan.ac.kr

Activating signal cointegrator-2 (ASC-2), a novel coactivator, is amplified in several cancer cells and known to interact with mitogenic transcription factors, including serum response factor, activating protein-1, and nuclear factor-B, suggesting the physiological role of ASC-2 in the promotion of cell proliferation. Here, we show that the expression pattern of ASC-2 was correlated with that of E2F-1 for protein increases at G₁ and S phase. Furthermore, cells stably overexpressing ASC-2 had an increased cell proliferation profile. These results prompted us to examine the functional interaction of ASC-2 and E2F-1. Biochemical evidence of protein interaction indicated that the transactivation domain of E2F-1 interacted with the COOH-terminal region of ASC-2. The importance of the E2F-1-ASC-2 interaction was supported by the demonstration that the coexpression of ASC-2 and E2F-1 synergistically transactivated E2F-1-driven gene transcription and the acetylation of E2F-1 protein was necessary for ASC-2-mediated transcriptional coactivation. Interestingly, overexpression of ASC-2 increased the endogenous protein level of E2F-1 in cells, resulting from the prolonged protein stability of E2F-1. Taken together, these results suggest that the cancer-amplified transcriptional coactivator ASC-2 may promote cell proliferation through enhancement of E2F-1-dependent transactivation of the expression of genes associated with cell cycle progression that may be available to favor tumor growth in vivo.

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