Young Arthur P, Longmore Gregory D
Department of Medicine, Washington University School of Medicine, 4940 Parkview Place, St Louis, MO 63110, USA.
Oncogene. 2004 Apr 8;23(15):2587-99. doi: 10.1038/sj.onc.1207330.
The retinoblastoma protein (Rb) controls cellular proliferation and suppresses tumor formation through its effects upon E2F transcriptional regulation of the cell cycle. Unexpectedly, however, in proliferating human cells, Rb was present at the promoters of eight of eight E2F-regulated apoptotic genes tested, but zero of six E2F-regulated cell cycle genes tested. Binding of apoptotic gene promoters by Rb was constitutive, and inhibition of Rb in human cells by E2Fdb or E1A expression resulted in induction of these apoptotic genes and efficient cell death. E1A induced apoptosis much more efficiently in human fibroblasts than in mouse fibroblasts, suggesting a difference in susceptibility to loss of Rb function between human cells and mouse cells. Abrogation of Rb function in mouse cells did not induce expression of these apoptotic genes. Underlying this species difference in susceptibility to apoptosis following loss of Rb function was the absence of Rb on apoptotic gene promoters in mouse cells. Rb protein levels were 20-35-fold higher in primary human cells than in primary mouse cells. The constitutive repression of a multitude of apoptotic genes by Rb in human cells but not in mouse cells may provide a partial explanation for the well-known difference between human and mouse cells in transformation and tumorigenic potential.
视网膜母细胞瘤蛋白（Rb）通过对细胞周期的E2F转录调控作用来控制细胞增殖并抑制肿瘤形成。然而，出乎意料的是，在增殖的人类细胞中，在所检测的8个E2F调控的凋亡基因的启动子上均存在Rb，但在所检测的6个E2F调控的细胞周期基因的启动子上Rb的存在率为零。Rb与凋亡基因启动子的结合是组成性的，通过E2Fdb或E1A表达抑制人类细胞中的Rb会导致这些凋亡基因的诱导和有效的细胞死亡。E1A在人类成纤维细胞中诱导凋亡比在小鼠成纤维细胞中更有效，这表明人类细胞和小鼠细胞对Rb功能丧失的敏感性存在差异。在小鼠细胞中消除Rb功能不会诱导这些凋亡基因的表达。Rb功能丧失后在凋亡敏感性上的这种物种差异的根本原因是小鼠细胞中凋亡基因启动子上不存在Rb。人类原代细胞中的Rb蛋白水平比小鼠原代细胞高20 - 35倍。Rb在人类细胞而非小鼠细胞中对多种凋亡基因的组成性抑制可能为人类细胞和小鼠细胞在转化和致瘤潜能方面的众所周知的差异提供部分解释。
