PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells.
PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells.
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DOI：
10.3390/cells12152008
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发表时间：
2023-08-05
期刊：
影响因子：
6
通讯作者：
Liu, Rui-Ming
中科院分区：
文献类型：
--
作者：
Rana, Tapasi;Jiang, Chunsun;Banerjee, Sami;Yi, Nengjun;Zmijewski, Jaroslaw W.;Liu, Gang;Liu, Rui-Ming
细胞衰老是衰老和衰老相关疾病的重要因素，包括特发性肺纤维化（IPF）。肺泡上皮II型（ATII）细胞是肺泡上皮的祖细胞，在IPF中ATII细胞衰老明显。本实验室之前的研究表明，丝氨酸蛋白酶抑制剂纤溶酶原激活物抑制剂1 （PAI-1）的表达增加，通过诱导主细胞周期抑制因子p53和激活p53-p21- prb细胞周期抑制通路，促进ATII细胞衰老。在本研究中，我们进一步发现PAI-1与蛋白酶体成分结合，抑制人肺上皮A549细胞和小鼠原代ATII细胞中蛋白酶体活性和p53降解。这与这些细胞的衰老表型有关，表现为p53和p21表达增加，磷酸化的视网膜母细胞瘤蛋白（pRb）降低，衰老相关的β-半乳糖（SA-β-gal）活性增加。此外，我们发现，尽管过度表达野生型PAI-1 （wtPAI-1）或分泌不足的成熟型PAI-1 （sdPAI-1）单独诱导ATII细胞衰老（增加SA-β-gal活性），但只有wtPAI-1诱导p53，这表明PAI-1的过早形式是与蛋白酶体相互作用所必需的。综上所述，我们的数据表明PAI-1可以结合蛋白酶体成分，从而抑制ATII细胞中的蛋白酶体活性和p53降解。由于p53是一种主细胞周期抑制因子，并且PAI-1在许多衰老细胞中表达增加，因此本研究结果不仅对ATII细胞衰老/肺纤维化有重要影响，而且对不同疾病中其他类型细胞的衰老也有重要影响。
Cellular senescence contributes importantly to aging and aging-related diseases, including idiopathic pulmonary fibrosis (IPF). Alveolar epithelial type II (ATII) cells are progenitors of alveolar epithelium, and ATII cell senescence is evident in IPF. Previous studies from this lab have shown that increased expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, promotes ATII cell senescence through inducing p53, a master cell cycle repressor, and activating p53-p21-pRb cell cycle repression pathway. In this study, we further show that PAI-1 binds to proteasome components and inhibits proteasome activity and p53 degradation in human lung epithelial A549 cells and primary mouse ATII cells. This is associated with a senescence phenotype of these cells, manifested as increased p53 and p21 expression, decreased phosphorylated retinoblastoma protein (pRb), and increased senescence-associated beta-galactose (SA-β-gal) activity. Moreover, we find that, although overexpression of wild-type PAI-1 (wtPAI-1) or a secretion-deficient, mature form of PAI-1 (sdPAI-1) alone induces ATII cell senescence (increases SA-β-gal activity), only wtPAI-1 induces p53, suggesting that the premature form of PAI-1 is required for the interaction with the proteasome. In summary, our data indicate that PAI-1 can bind to proteasome components and thus inhibit proteasome activity and p53 degradation in ATII cells. As p53 is a master cell cycle repressor and PAI-1 expression is increased in many senescent cells, the results from this study will have a significant impact not only on ATII cell senescence/lung fibrosis but also on the senescence of other types of cells in different diseases.
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DOI：
10.1073/pnas.1120437109
发表时间：
2012-07-24
影响因子：
11.1
作者：
Elzi, David J.;Lai, Yanlai;Shiio, Yuzuru
通讯作者：
Shiio, Yuzuru
截短的纤溶酶原激活剂抑制剂-1蛋白可以保护鼠模型中辐射介导的肺纤维化。
DOI：
10.1016/j.ijrobp.2015.11.044
发表时间：
2016-04-01
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
Chung EJ;McKay-Corkum G;Chung S;White A;Scroggins BT;Mitchell JB;Mulligan-Kehoe MJ;Citrin D
通讯作者：
Citrin D
影响因子：
3.7
作者：
Disayabutr S;Kim EK;Cha SI;Green G;Naikawadi RP;Jones KD;Golden JA;Schroeder A;Matthay MA;Kukreja J;Erle DJ;Collard HR;Wolters PJ
通讯作者：
Wolters PJ
影响因子：
4.8
作者：
Boncela, Joanna;Przygodzka, Patrycja;Cierniewski, Czeslaw S.
通讯作者：
Cierniewski, Czeslaw S.
影响因子：
7.4
作者：
Jiang, Chun-Sun;Rana, Tapasi;Jin, Lee-Way;Farr, Susan A.;Morley, John E.;Qin, Hongwei;Liu, Gang;Liu, Rui-Ming
通讯作者：
Liu, Rui-Ming