The CBP co-activator stimulates E2F1/DP1 activity.
The CBP co-activator stimulates E2F1/DP1 activity.
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CBP 共激活剂刺激 E2F1/DP1 活性。
DOI：
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发表时间：
1996
影响因子：
14.9
通讯作者：
T. Kouzarides
中科院分区：
文献类型：
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作者：
D. Trouche;A. Cook;T. Kouzarides
细胞周期调节转录因子E2 F1/DP 1激活其产物为S期进展所需的基因。在大多数G1期，E2 F1/DP 1活性被视网膜母细胞瘤基因产物RB抑制，RB直接接触E2 F1激活结构域并使其沉默。E2 F1激活结构域与E1 A（12 S）的N-末端激活结构域具有序列相似性，其含有CBP和RB的结合位点。在这里，我们提出的证据表明，CBP蛋白直接接触E2 F1/DP 1，并刺激其激活能力。我们发现CBP在体外和体内都与E2 F1的激活结构域相互作用。从E2 F1激活结构域中删除四个残基降低CBP结合以及转录激活，但仍然允许RB和MDM 2的结合。该缺失去除了E1 A的N-末端活化结构域中保守的残基，并且这些残基是CBP与E1 A结合所需的。当E1 A的N-末端被用作在压制实验中的竞争对手，它废除CBP诱导的E2 F1/DP 1的激活，而E1 A突变体缺乏CBP结合能力不能做到这一点。这些结果表明CBP可以作为E2 F1的共激活剂，并表明CBP识别E1 A和E2 F1激活结构域内的相似基序。RB和CBP途径在E2 F1活性调节上的趋同性可以解释这些蛋白在介导E1 A的生物学功能中所显示的协同性。我们提出了一个模型，其中E1 A激活E2 F不仅通过消除RB的镇压，但也通过提供CBP的辅激活剂。
The cell cycle-regulating transcription factors E2F1/DP1 activate genes whose products are required for S phase progression. During most of the G1 phase, E2F1/DP1 activity is repressed by the retinoblastoma gene product RB, which directly contacts the E2F1 activation domain and silences it. The E2F1 activation domain has sequence similarity to the N-terminal activation domain of E1A(12S), which contains binding sites for CBP as well as RB. Here, we present evidence that the CBP protein directly contacts E2F1/DP1 and stimulates its activation capacity. We show that CBP interacts with the activation domain of E2F1 both in vitro and in vivo. Deletion of four residues from the E2F1 activation domain reduces CBP binding as well as transcriptional activation, but still allows the binding of RB and MDM2. This deletion removes residues which are conserved in the N-terminal activation domain of E1A and which are required for the binding of CBP to E1A. When the E1A N-terminus is used as a competitor in squelshing experiments it abolishes CBP-induced activation of E2F1/DP1, whereas an E1A mutant lacking CBP binding ability fails to do so. These results indicate that CBP can act as a coactivator for E2F1 and suggest that CBP recognises a similar motif within the E1A and E2F1 activation domains. The convergence of the RB and CBP pathways on the regulation of E2F1 activity may explain the cooperativity displayed by these proteins in mediating the biological functions of E1A. We propose a model in which E1A activates E2F not only by removing the RB repression but also by providing the CBP co-activator.