Yamasaki L, Bronson R, Williams B O, Dyson N J, Harlow E, Jacks T
Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Nat Genet. 1998 Apr;18(4):360-4. doi: 10.1038/ng0498-360.
Mutation of the retinoblastoma tumour-suppressor gene (RB) leads to the deregulation of many proteins and transcription factors that interact with the retinoblastoma gene product (pRB), including members of the E2F transcription factor family. As pRB is known to repress E2F transcriptional activity and overexpression of E2F is sufficient for cell cycle progression, it is thought that pRB suppresses growth in part by repressing E2F-mediated transcription. Previously, we reported that loss of E2f1 in mice results in tissue-specific tumour induction and tissue atrophy, demonstrating that E2F-1 normally controls growth both positively and negatively in a tissue-specific fashion. To determine whether E2F-1 deregulation--as a result of loss of pRB--promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/-) mice. We have found that loss of E2f1 reduces the frequency of pituitary and thyroid tumours, and greatly lengthens the lifespan of Rb1(+/-); E2f1(-/-) animals, demonstrating that E2F-1 is an important downstream target of pRB during tumorigenesis. Furthermore, loss of E2f1 reduces a previously reported strain-dependent difference in Rb1(+/-) lifespan, suggesting that E2f1 or an E2F-1-regulated gene acts as a genetic modifier between the 129/Sv and C57BL/6 strains.
视网膜母细胞瘤肿瘤抑制基因（RB）的突变会导致许多与视网膜母细胞瘤基因产物（pRB）相互作用的蛋白质和转录因子失调，其中包括E2F转录因子家族的成员。由于已知pRB可抑制E2F的转录活性，且E2F的过表达足以促进细胞周期进程，因此人们认为pRB部分通过抑制E2F介导的转录来抑制生长。此前，我们报道过小鼠中E2f1的缺失会导致组织特异性肿瘤诱导和组织萎缩，这表明E2F-1通常以组织特异性方式对生长进行正向和负向控制。为了确定由于pRB缺失导致的E2F-1失调是否会在体内促进增殖，我们测试了E2f1的缺失是否会干扰Rb1(+/-)小鼠中发生的垂体和甲状腺肿瘤发生。我们发现E2f1的缺失降低了垂体和甲状腺肿瘤的发生率，并大大延长了Rb1(+/-); E2f1(-/-)动物的寿命，这表明E2F-1是肿瘤发生过程中pRB的一个重要下游靶点。此外，E2f1的缺失减少了先前报道的Rb1(+/-)寿命中的品系依赖性差异，这表明E2f1或一个受E2F-1调控的基因在129/Sv和C57BL/6品系之间充当遗传修饰因子。
