Transforming growth factor beta 1 (TGF beta 1) reduces cellular levels of p34cdc2, and this effect is abrogated by adenovirus independently of the E1A-associated pRB binding activity.
Transforming growth factor beta 1 (TGF beta 1) reduces cellular levels of p34cdc2, and this effect is abrogated by adenovirus independently of the E1A-associated pRB binding activity.
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DOI：
10.1091/mbc.3.6.655
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发表时间：
1992-06
影响因子：
3.3
通讯作者：
S. Abraham;M C Carter;E. Moran
中科院分区：
文献类型：
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作者：
S. Abraham;M C Carter;E. Moran
我们使用E1A探针研究了p34cdc2激酶和视网膜母细胞瘤肿瘤易感基因产物（pRB）在转化生长因子β 1（TGF β 1）介导的水貂肺上皮（Mv1Lu）细胞生长抑制中的作用。与以前的报道一致，我们看到TGF β 1处理后p34cdc2激酶活性下降，pRB磷酸化丧失。我们在这里报告，TGF β 1诱导不仅在p34cdc2激酶活性的变化，但p34cdc2合成的强烈抑制。直到p34cdc2的稳态水平下降，才观察到p34cdc2激酶活性的丧失，这表明TGF β 1诱导的细胞内信号在表达水平上影响p34cdc2，而不是通过改变p34cdc2的翻译后修饰来调节其激酶活性。用表达野生型E1A或pRB结合缺陷的突变型E1A（pm928）的腺病毒感染减轻了TGF β 1介导的DNA合成抑制，表明E1A不需要物理结合pRB来保持细胞生长抑制功能不被TGF β 1激活。E1A.928突变体病毒能够维持p34cdc2表达和激酶活性，以及在TGF β 1存在下的pRB磷酸化，这可以解释其维持细胞周期活性而不直接螯合pRB的能力。总体而言，我们的研究结果表明，TGF β 1的作用信号的变化在G1基因表达的控制水平，而不是在翻译后修饰的p34cdc2或其底物的水平。
We have used E1A probes to study the roles of the p34cdc2 kinase and the retinoblastoma tumor susceptibility gene product (pRB) in transforming growth factor beta 1 (TGF beta 1)-mediated growth suppression in mink lung epithelial (Mv1Lu) cells. In agreement with previous reports, we see a decline in p34cdc2 kinase activity and a loss of pRB phosphorylation after TGF beta 1 treatment. We report here that TGF beta 1 induces not only a change in p34cdc2 kinase activity but a strong repression of p34cdc2 synthesis. Loss of p34cdc2 kinase activity is not seen until the steady-state level of p34cdc2 declines, suggesting that the intra-cellular signals induced by TGF beta 1 affect p34cdc2 at the level of expression, rather than by altering the posttranslational modifications of p34cdc2 that regulate its kinase activity. Infection with adenovirus expressing either wild-type E1A or a mutant E1A (pm928) defective for pRB binding alleviated TGF beta 1-mediated suppression of DNA synthesis, indicating that E1A does not need to bind pRB physically to keep cell growth-suppressing functions from being activated by TGF beta 1. The E1A.928 mutant virus is able to maintain p34cdc2 expression and kinase activity, as well as pRB phosphorylation in the presence of TGF beta 1, which may account for its ability to maintain cell cycle activity without directly sequestering pRB. Overall our results suggest that TGF beta 1 acts by signaling changes at the level of control of G1 gene expression, not at the level of posttranslational modification of p34cdc2 or its substrates.