Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency.
Loss of p21 promoted tumorigenesis in the background of telomere dysfunctions induced by TRF2 and Wrn deficiency.
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TRF2 和 Wrn 缺陷导致端粒功能障碍，p21 缺失促进肿瘤发生
DOI：
10.7150/ijbs.23477
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发表时间：
2018
影响因子：
9.2
通讯作者：
Luo Y
中科院分区：
文献类型：
--
作者：
Si X;Shao C;Li J;Jia S;Tang W;Zhang J;Yang J;Wu X;Luo Y
Werner综合征（WS）是一种罕见的常染色体隐性遗传性早老症，具有遗传不稳定性和癌症易感性，是研究衰老相关癌症的良好模型。端粒功能障碍诱导的细胞衰老在WS表型的表现中是必不可少的。我们的前期研究表明，Cdkn 1a基因编码的p21可以诱导WS细胞的衰老，并抑制其ALT（alternative elongation of telomere）肿瘤的生长，提示p21可能在维持WS细胞衰老中起关键作用。为了证实p21在抑制端粒功能障碍诱导的肿瘤发生中的作用，我们在p21-/-小鼠胚胎成纤维细胞（MEFs）中过表达显性负性蛋白TRF 2 ΔBΔM。为了进一步应激细胞，我们将p21-/-小鼠与p21-/-小鼠杂交以获得p21-/-p21-/-p21-/- MEFs，并在这些MEFs中过表达TRF 2 ΔBΔM以诱导类似于WS细胞中的端粒功能障碍。我们的数据表明，在p21-/-TRF 2 ΔBΔM的背景下，p21功能的丧失挽救了细胞衰老，并诱导了p53突变，但不诱导肿瘤发生。而在p21-/-TRF 2 ΔBΔM组中，p21功能的缺失导致p53突变和肿瘤发生。为了进一步验证p21在抑制端粒功能障碍相关的肿瘤发生中的作用，我们敲低了来源于WS MEFs（mTerc-/-cnn-/-）的非致瘤性永生化细胞中的p21，发现p21的缺失可以诱导ALT肿瘤发生，其显示典型的端粒长度和弧形端粒DNA的涂片模式。另一方面，在这些MEFs中恢复端粒酶活性也可以诱导肿瘤发生，而不影响p21表达水平。总之，我们的数据表明，p21控制的细胞周期调控在抑制端粒功能障碍相关的肿瘤发生中发挥了重要作用。这些数据还表明，遗传背景在决定p21在癌症预防中的作用方面至关重要。因此，在人类退行性疾病的治疗中靶向p21将需要个性化的遗传背景筛选。
Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells. To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2ΔBΔM in p21-/- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn-/-mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2ΔBΔM in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/-TRF2ΔBΔM, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/-TRF2ΔBΔM, loss of p21 function induced p53 mutation and tumorigenesis. To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc-/-Wrn-/-), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
30.8
作者：
Broccoli, D;Smogorzewska, A;deLange, T
通讯作者：
deLange, T
影响因子：
8
作者：
Pantoja, C;Serrano, M
通讯作者：
Serrano, M
影响因子：
30.8
作者：
Choudhury, Aaheli Roy;Ju, Zhenyu;Rudolph, K. Lenhard
通讯作者：
Rudolph, K. Lenhard