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.
Highlights
Protein phosphorylation/dephosphorylation is one of the most important post-translational modifications, modulating functions of more than one-third of total eukaryote proteins, and participates in control of various physiological processes such as gene expression and regulation, DNA replication and damage response, cell proliferation, growth and differentiation, cell transformation, and apoptosis (Cohen, 1989; Hunter, 1995; Hunter & Karin, 1992; Moorhead et al, 2007; Mumby & Walter, 1993; Olsen et al, 2006).It is well established that protein phosphorylation/dephosphorylation is implicated in control of cell senescence and organism aging
Our results demonstrate that dephosphorylation by PP-1β and PP-2Aα modulates cAMP response element-binding protein (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 lenses
We have demonstrated the followings: (1) Treatment of both lens epithelial cells, mouse lens epithelial cells (αTN4-1) and mouse skin epithelial cells, JB6 with different concentrations of okadaic acid (OA) or LB100 causes dose-dependent hyperphosphorylation of CREB at S133; (2) Silence of PP-1β and PP-2Aα causes hyperphosphorylation of CREB at S133; (3) Overexpression of PP-1β and PP-2Acα through the Tet-on system leads to complete dephosphorylation of CREB
Summary
Protein phosphorylation/dephosphorylation is one of the most important post-translational modifications, modulating functions of more than one-third of total eukaryote proteins, and participates in control of various physiological processes such as gene expression and regulation, DNA replication and damage response, cell proliferation, growth and differentiation, cell transformation, and apoptosis (Cohen, 1989; Hunter, 1995; Hunter & Karin, 1992; Moorhead et al, 2007; Mumby & Walter, 1993; Olsen et al, 2006). By suppressing expression of αB-crystallin in lens epithelial cells, CREB promotes oxidative stress-induced apoptosis followed by cataractogenesis (Li et al, 1995; Li & Spector, 1996; Wang et al, 2020). We demonstrate that CREB regulates aging process through suppression of αB-crystallin and activation of the p300-p53-Bak/Bax signaling axis. We showed that lens epithelial cells expressing the S133A-CREB, a mutant mimicking constant dephosphorylation of CREB at S133, suppress the ability of wild-type CREB in mediating aging control and stress response. Our results demonstrate that dephosphorylation by PP-1β and PP-2Aα modulates 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 lenses
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