@article{30bde31c1f314f83ae0387149da98018,
title = "PP-1β and PP-2Aα modulate cAMP response element-binding protein (CREB) functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53 signaling axis",
abstract = "The function of the transcription factor, cAMP response element-binding protein (CREB), is activated through S133 phosphorylation by PKA and others. Regarding its inactivation, it is not well defined. cAMP response element-binding protein plays an essential role in promoting cell proliferation, neuronal survival and the synaptic plasticity associated with long-term memory. Our recent studies have shown that CREB is an important player in mediating stress response. Here, we have demonstrated that CREB regulates aging process through suppression of αB-crystallin and activation of the p300-p53-Bak/Bax signaling axis. First, we determined that two specific protein phosphatases, PP-1β and PP-2Aα, can inactivate CREB through S133 dephosphorylation. Subsequently, we demonstrated that cells expressing the S133A-CREB, a mutant mimicking constant dephosphorylation at S133, suppress CREB functions in aging control and stress response. Mechanistically, S133A-CREB not only significantly suppresses CREB control of αB-crystallin gene, but also represses CREB-mediated activation of p53 acetylation and downstream Bak/Bax genes. cAMP response element-binding protein suppression of αB-crystallin and its activation of p53 acetylation are major molecular events observed in human cataractous lenses of different age groups. Together, our results demonstrate that PP-1β and PP-2Aα modulate CREB functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53-Bax/Bak signaling axis, which regulates human cataractogenesis in the aging lens.",
keywords = "Bak, Bax, P300, PP-1β; PP-2Aα; CREB, Pcaf, aging, apoptosis, cataract, oxidative stress, p53",
author = "Ling Wang and Lan Zhang and Gong, {Xiao Dong} and Fu, {Jia Ling} and Gan, {Yu Wen} and Min Hou and Qian Nie and Xiang, {Jia Wen} and Yuan Xiao and Yan Wang and Zheng, {Shu Yu} and Lan Yang and Huimin Chen and Xiang, {Meng Qing} and Yizhi Liu and Li, {David Wan Cheng}",
note = "Funding Information: This study was supported in part by the NSFC Grants of China (#81900842; #81770910; #81970787; and #82000876), the Joint Key Project of Natural Science Foundation of Ophthalmology in Guangdong Province and Guangzhou City (2019B1515120014), and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology in Zhongshan Ophthalmic Center, Sun Yat-sen University (3030901010111 and 303060202400201098) We thank Dr. Paul Russel for the αTN4-1 mouse lens epithelial cell line, Dr. Zigang Dong for the JB6 cells, Dr. Joseph Horwitz for the anti-αB-crystallin antibody, Dr. Mingxing Wu, Dr. Bing Cheng, Dr. Weirong Chen, Dr. Lixia Luo, Dr. Xinyu Zhang, Dr. Xialin Liu, Dr. Danying Zheng, Dr. Shengsong Huang for providing capsular epithelia from patients at surgery, and all members of David Li's Laboratory in the State Key Laboratory of Ophthalmology in Zhongshan Ophthalmic Center of Sun Yat-sen University. Funding Information: This study was supported in part by the NSFC Grants of China (#81900842; #81770910; #81970787; and #82000876), the Joint Key Project of Natural Science Foundation of Ophthalmology in Guangdong Province and Guangzhou City (2019B1515120014), and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology in Zhongshan Ophthalmic Center, Sun Yat‐sen University (3030901010111 and 303060202400201098) Publisher Copyright: {\textcopyright} 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",
year = "2021",
month = sep,
doi = "10.1111/acel.13458",
language = "English (US)",
volume = "20",
journal = "Aging cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "9",
}