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首页> 外文期刊>Molecular and Cellular Biology >Establishment of Irreversible Growth Arrest in Myogenic Differentiation Requires the RB LXCXE-Binding Function
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Establishment of Irreversible Growth Arrest in Myogenic Differentiation Requires the RB LXCXE-Binding Function

机译：建立成肌分化中不可逆的生长停滞需要RB LXCXE结合功能

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The crystal structure of the A-B domain of RB has defined the binding pocket for the LXCXE peptide motif. Using the crystal structure as a guide, we have inactivated the LXCXE-binding pocket by replacing N757 with Phe [to obtain RB(N757F)]. RB(N757F) does not bind to viral oncoproteins but retains the ability to bind and inhibit E2F. RB(N757F) is less effective than the wild-type RB [RB(WT)] in repressing E2F-regulated transcription, and its repression activity is not affected by trichostatin A, an inhibitor of histone deacetylases. However, RB(N757F) is as effective as RB(WT) in suppressing cell growth. Interestingly, RB(N757F) cannot establish an irreversible growth arrest in differentiated myocytes. Differentiated myocytes with RB(WT) become refractory to serum. By contrast, differentiated myocytes with RB(N757F) undergo DNA synthesis and phosphorylate RB(N757F) in response to serum, despite a high level of p21Cip1 expression. Mutation of the phosphorylation sites in RB(N757F) rescued its defect and allowed myocytes to permanently withdraw from the cell cycle. These results demonstrate that it is possible to inactivate the LXCXE-binding pocket without compromising the overall integrity of RB. Moreover, the LXCXE-binding pocket is dispensable for the intrinsic growth suppression function of RB. However, the LXCXE-binding function is essential for RB to establish the serum-refractory state in differentiated myocytes.
机译：RB的A-B结构域的晶体结构已经定义了LXCXE肽基序的结合口袋。使用晶体结构作为指导，我们通过用Phe代替N757来失活了LXCXE结合口袋[以获得RB（N757F）]。 RB（N757F）不结合病毒癌蛋白，但保留结合和抑制E2F的能力。 RB（N757F）在抑制E2F调节的转录方面不如野生型RB [RB（WT）]有效，并且其抑制活性不受组蛋白脱乙酰基酶抑制剂曲古抑菌素A的影响。但是，RB（N757F）在抑制细胞生长方面与RB（WT）一样有效。有趣的是，RB（N757F）无法在分化的心肌细胞中建立不可逆的生长停滞。具有RB（WT）的分化的心肌细胞对血清变得难治。相比之下，尽管p21Cip1的表达水平很高，具有RB（N757F）的分化的心肌细胞仍会进行DNA合成，并使RB（N757F）磷酸化以响应血清。 RB（N757F）中磷酸化位点的突变挽救了它的缺陷，并使心肌细胞永久退出细胞周期。这些结果表明，可以在不损害RB整体完整性的情况下使LXCXE结合口袋失活。此外，LXCXE结合袋对于RB的固有生长抑制功能是必不可少的。但是，LXCXE结合功能对于RB在分化的心肌细胞中建立血清不应性状态至关重要。

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