Johnson D G, Cress W D, Jakoi L, Nevins J R
Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12823-7. doi: 10.1073/pnas.91.26.12823.
Previous experiments have identified the E2F transcription factor as a potential downstream target for the action of cellular regulatory activities, such as the Rb tumor suppressor protein, that control cell growth and that, when altered, contribute to the development of human tumors. In light of these findings, we have assayed the ability of the E2F1 and DP1 genes, which encode heterodimeric partners that together create E2F activity, to act in an oncogenic fashion. We find that E2F1, particularly in combination with the DP1 product, cooperates with an activated ras oncogene to induce the formation of morphologically transformed foci in primary rat embryo fibroblast cultures. In addition, an E2F1 chimeric protein, in which sequences involved in Rb binding have been replaced with the herpesvirus VP16 activation domain, exhibits increased transformation activity. Cells transfected with E2F1 and DP1 or the E2F1-VP16 chimera form colonies in soft agar and induce tumor formation in nude mice. We conclude that deregulated E2F1 expression and function can have oncogenic consequences.
先前的实验已确定E2F转录因子是细胞调节活动（如Rb肿瘤抑制蛋白）作用的潜在下游靶点，这些调节活动控制细胞生长，一旦发生改变，就会促进人类肿瘤的发生。鉴于这些发现，我们检测了E2F1和DP1基因（它们编码共同产生E2F活性的异二聚体伙伴）以致癌方式发挥作用的能力。我们发现，E2F1，特别是与DP1产物结合时，能与激活的ras癌基因协同作用，在原代大鼠胚胎成纤维细胞培养物中诱导形成形态转化灶。此外，一种E2F1嵌合蛋白（其中与Rb结合的序列已被疱疹病毒VP16激活域取代）表现出增强的转化活性。用E2F1和DP1或E2F1-VP16嵌合体转染的细胞在软琼脂中形成菌落，并在裸鼠中诱导肿瘤形成。我们得出结论，E2F1表达和功能失调可产生致癌后果。
