Tevosian S G, Shih H H, Mendelson K G, Sheppard K A, Paulson K E, Yee A S
The Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Genes Dev. 1997 Feb 1;11(3):383-96. doi: 10.1101/gad.11.3.383.
A prominent feature of cell differentiation is the initiation and maintenance of an irreversible cell cycle arrest with the complex involvement of the retinoblastoma (RB) family (RB, p130, p107). We have isolated the HBP1 transcriptional repressor as a potential target of the RB family in differentiated cells. By homology, HBP1 is a sequence-specific HMG transcription factor, of which LEF-1 is the best-characterized family member. Several features of HBP1 suggest an intriguing role as a transcriptional and cell cycle regulator in differentiated cells. First, inspection of the HBP1 protein sequence revealed two consensus RB interaction motifs (LXCXE and IXCXE). Second, HBP1 interaction was selective for RB and p130, but not p107. HBP1, RB, and p130 levels are all up-regulated with differentiation; in contrast, p107 levels decline. Third, HBP1 can function as a transcriptional repressor of the promoter for N-MYC, which is a critical cell cycle and developmental gene. Fourth, because the activation of the N-MYC promoter in cycling cells required the E2F transcription factor, we show that E2F-1 and HBP1 represent opposite transcriptional signals that can be integrated within the N-MYC promoter. Fifth, the expression of HBP1 lead to efficient cell cycle arrest. The arrest phenotype was manifested in the presence of optimal proliferation signals, suggesting that HBP1 exerted a dominant regulatory role. Taken together, the results suggest that HBP1 may represent a unique transcriptional repressor with a role in initiation and establishment of cell cycle arrest during differentiation.
细胞分化的一个显著特征是不可逆的细胞周期停滞的启动和维持，这一过程涉及视网膜母细胞瘤（RB）家族（RB、p130、p107）的复杂参与。我们已分离出HBP1转录抑制因子，作为分化细胞中RB家族的潜在靶点。通过同源性分析，HBP1是一种序列特异性的HMG转录因子，其中LEF-1是特征最明确的家族成员。HBP1的几个特征表明它在分化细胞中作为转录和细胞周期调节因子具有有趣的作用。首先，对HBP1蛋白序列的检查揭示了两个一致的RB相互作用基序（LXCXE和IXCXE）。其次，HBP1与RB和p130的相互作用具有选择性，而与p107没有相互作用。随着分化，HBP1、RB和p130的水平均上调；相反，p107的水平下降。第三，HBP1可作为N-MYC启动子的转录抑制因子，N-MYC是一个关键的细胞周期和发育基因。第四，由于在循环细胞中N-MYC启动子的激活需要E2F转录因子，我们表明E2F-1和HBP1代表相反的转录信号，它们可整合在N-MYC启动子内。第五，HBP1的表达导致有效的细胞周期停滞。在存在最佳增殖信号的情况下出现停滞表型，这表明HBP1发挥了主导调节作用。综上所述，结果表明HBP1可能代表一种独特的转录抑制因子，在分化过程中细胞周期停滞的启动和建立中发挥作用。
