CREB Regulates Acetyl-Transferases To Control Stress-Induced Apoptosis In Lens

Cataract is the leading cause for the blindness of human in the world.The current treatment for cataracts is mainly through surgical operation plus implantation of the artificial lens.However,the postoperative complications of cataract patients cause vision loss and economic burden.Thus,elucidation of the mechanisms for cataractogenesis is particularly important.Except for genetic cataracts,apoptosis has been proven to be an important cell biology basis for stress-induced non-genetic cataracts.The general transcription factor of CREB has been shown to play an essential role in promoting cell proliferation,neuronal survival and synaptic plasticity in the nervous system.In our recent studies,we have shown that CREB plays an important role in regulating stress response.It can negatively regulate the expression of the anti-apoptotic factor,αBcrystallin gene to enhance the sensitivity of cells to external stimulation.In this thesis,we further prove that CREB has important function in controlling stress-induced apoptosis.First,CREB-expressing cells are more sensitive to apoptosis induced by oxidative stress in mouse lens epithelial cells.Second,western blot analysis(WB)reveals that CREB can significantly up-regulates expression of the pro-apoptotic genes encoding Bak and Bax through enhanced acetylation of the tumor suppressor p53.To further explore the molecular mechanism by which CREB regulates acetylation of p53,we have analyzed the expression patterns of four common acetylases P300、CBP、PCAF and GCN5 at the protein level.Our results show that CREB can up-regulate expression of the four acetylases.In addition,CREB can bind to the enhancer elements of CBP、PCAF and GCN5 promoters to regulate their expression as verified through in vitro EMSA experiments and in vivo Ch IP assay.In conclusion,our results support that CREB is an important regulator of stress response.It can directly regulate the expression of P300、CBP、PCAF and GCN5 to enhance p53 acetylation and then upregulate the proapoptotic factors bak and bax,leading to enhanced sensitivities of the lens epithelial cells to oxidative stress-induced apoptosis.