Open AccessPP‐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
Author(s) -
Wang Ling,
Zhang Lan,
Gong XiaoDong,
Fu JiaLing,
Gan YuWen,
Hou Min,
Nie Qian,
Xiang JiaWen,
Xiao Yuan,
Wang Yan,
Zheng ShuYu,
Yang Lan,
Chen Huimin,
Xiang MengQing,
Liu Yizhi,
Li David WanCheng
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13458
Subject(s) - creb , dephosphorylation , cyclic amp response element binding protein , biology , creb binding protein , microbiology and biotechnology , phosphorylation , creb1 , transcription factor , phosphatase , gene , genetics
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.