Loss of the hSNF5 gene concomitantly inactivates p21CIP/WAF1 and p16INK4a activity associated with replicative senescence in A204 rhabdoid tumor cells
Loss of the hSNF5 gene concomitantly inactivates p21CIP/WAF1 and p16INK4a activity associated with replicative senescence in A204 rhabdoid tumor cells
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DOI：
10.1158/0008-5472.can-05-1896
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Weissman, BE
中科院分区：
文献类型：
--
作者：
Chai, JJ;Charboneau, AL;Weissman, BE
hSNF 5是SWI/SNF染色质重塑复合物的最小成员，在大多数恶性横纹肌样瘤（MRT）中丢失。在MRT细胞系中，hSNF 5的再表达诱导G、细胞周期停滞、升高的p16（INK 4a）和活化的复制性衰老标志物，如β-半乳糖苷酶（β-Gal）和纤溶酶原激活物抑制剂-1。为了比较A204细胞中由hSNF 5引起的复制性衰老与正常细胞衰老，我们检测了p16（INK 4a）和p21（CIP/WAF 1）的激活。与正常细胞衰老类似，p16（INK 4a）和p21（CIP/WAF 1）在hSNF 5恢复后均上调。此外，我们发现hSNF 5结合P16（INK 4a）和p21（CIP/WAF 1）启动子，表明它直接调节这些基因的转录。使用p16（INK 4a）RNA干扰，我们发现它需要hSNF 5引起的复制衰老，而不是生长停滞。相反，p21（CIP/WAFI）在不存在高p16（INK 4a）的情况下仍然被hSNF 5激活。表达，显然导致A204中的生长停滞。有趣的是，我们还发现，在p16（INK 4a）缺失的情况下，hSNF 5的再表达也增加了第二种细胞周期蛋白依赖性激酶（CDK）抑制剂p18（INK 4a）的蛋白水平。然而，我们的数据表明，缺乏hSNF 5并没有废除细胞对DNA损伤或生长抑制因子的反应。总之，我们的研究表明，hSNF 5的损失可能会影响多种CDK抑制剂参与复制性衰老的调节。
hSNF5, the smallest member of the SWI/SNF chromatin remodeling complex, is lost in most malignant rhabdoid tumors (MRT). In MRT cell lines, reexpression of hSNF5 induces G, cell cycle arrest, elevated p16(INK4a), and activated replicative senescence markers, such as beta-galactosidase (beta-Gal) and plasminogen activator inhibitor-1. To compare the replicative senescence caused by hSNF5 in A204 cells to normal cellular senescence, we examined the activation of both p16(INK4a) and p21(CIP/WAF1). Analogous to normal cellular senescence, both p16(INK4a) and p21(CIP/WAF1) were up-regulated following hSNF5 restoration. Furthermore, we found that hSNF5 bound the P16(INK4a) and p21(CIP/WAF1) promoters, suggesting that it directly regulates transcription of these genes. Using p16(INK4a) RNA interference, we showed its requirement for the replicative senescence caused by hSNF5 but not the growth arrest. Instead, p21(CIP/WAFI) remained activated by hSNF5 in the absence of high p16(INK4a). expression, apparently causing the growth arrest in A204. Interestingly, we also found that, in the absence of p16(INK4a), reexpression of hSNF5 also increased protein levels of a second cyclin-dependent kinase (CDK) inhibitor, p18(INK4a). However, our data show that lack of hSNF5 does not abrogate cellular responsiveness to DNA damage or growth-inhibitory factors. In summary, our studies suggest that hSNF5 loss may influence the regulation of multiple CDK inhibitors involved in replicative senescence.