cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

Abstract

Abstract. Activation of cAMP signalling potently inhibits DNA damage-induced apoptosis in acute lymphoblastic leukemia cells by promoting the turnover of p53 protein. Recently, we showed that the cAMP-induced destabilization of p53 in DNA-damaged cells occurs as a result of enhanced interaction between p53 and HDM2. In this report, we present results showing that increased levels of cAMP in cells with DNA damage enhances the deacetylation of p53, an event that facilitates the interaction of p53 with HDM2, thus annulling the stabilizing effect of DNA damage on p53. The combined inhibition of the HDAC and SIRT1 deacetylases abolished the cAMP-mediated deacetylation of p53, implying that cAMP-mediated deacetylation of p53 is dependent on the activity of these two classes of histone deacetylases. Importantly, diminishing the activity of HDACs and SIRT1 was also found to reverse the inhibitory effect of cAMP on the DNA damage-induced p53 stabilization and apoptosis, suggesting the involvement of the p53 acetylation pathway in the anti-apoptotic effect of cAMP signalling.

Gold-chrysophanol nanoparticles suppress human prostate cancer progression through inactivating AKT expression and inducing apoptosis and ROS generation in vitro and in vivo

“…According to previous studies, HDAC inhibitors are also reported to induce acetylation in non-histone proteins ( 31 ). For example, the HDAC1 inhibitor TSA leads to acetylation of p53 on K373 primarily under conditions in which cells are subjected to ionizing radiation, acting as a transcription factor regulating multiple genes important for the regulation of cell cycle arrest, senescence and apoptosis ( 32 ).…”

Resveratrol Induces the Expression of Interleukin-10 and Brain-Derived Neurotrophic Factor in BV2 Microglia under Hypoxia

“…Activation of NF-κB plays a central role in inflammation and exerts multiple effects in various cellular responses [ 72 ]. Several studies have demonstrated that resveratrol regulates the activity of apoptotic transcription factors and regulates inflammatory responses by modulating NF-κB [ 73 , 74 , 75 ]. Taken together, our data indicate that resveratrol may inhibit neuronal inflammatory responses by suppressing the activation of NF-κB in microglia under ischemic brain injury.…”

cAMP signaling inhibits radiation-induced ATM phosphorylation leading to the augmentation of apoptosis in human lung cancer cells

“…This finding also implies that drugs targeting the cAMP signaling pathway could be possibly used to modulate radiation-induced apoptosis, thereby increasing the radiosensitivity of cancer cells or protecting normal cells from radiation. The cAMP signaling system can stimulate or inhibit apoptosis depending on cell types [ 27 ] through diverse molecular mechanisms involving Bcl-2 family proteins, p53, and histone deacetylase [ 16 , 28 , 29 ]. Thus, this study presents a novel mechanism for the cAMP signaling system to regulate cancer cell apoptosis.…”

“…Recently, the cAMP signaling system was found to inhibit the repair of γ-ray-induced DNA damage by promoting degradation of the XRCC1 protein in human lung cancer cells [ 15 ]. The cAMP signaling system was also reported to inhibit DNA-damage induced apoptosis of leukemia cells by promoting acetylation and turnover of p53 [ 16 , 17 ]. Thus, we hypothesized that the cAMP signaling system might be involved in the regulation of ATM activation, the key event triggering signaling pathways in response to DNA damage.…”