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

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.

Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death.

With cAMP signaling having a profound inhibitory effect on DNA damage-induced apoptosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells, understanding how this signaling pathway affects the survival capacity of the cell has important implications for cancer therapy. We have recently shown that p53 is critical for the inhibitory effect of cAMP on genotoxic agents-mediated apoptosis in BCP-ALLs. Here, we show that elevation of cAMP levels in cells exposed to DNA damage enhances the nuclear translocation and DNA binding of NF-κB by accelerating the phosphorylation of IKKβ and thereby phosphorylation and degradation of IκBα.

EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase.

Cyclic AMP (cAMP) is an important physiological growth inhibitor of lymphoid cells, and the cAMP/protein kinase A (PKA) pathway is disrupted in several immunological disorders and cancers. Epstein Barr virus (EBV) infection of B lymphocytes is responsible for the development of lymphoproliferative disease as well as certain B-lymphoid malignancies. Here we hypothesized that EBV infection might render B lymphocytes resistant to cAMP/PKA-mediated growth inhibition.

Re-routing of the invariant chain to the direct sorting pathway by introduction of an AP3-binding motif from LIMP II.

AP3 is a heteromeric adaptor protein complex involved in the biogenesis of late endosomal/lysosomal structures. It recognizes tyrosine- and leucine-based sorting signals present in the cytoplasmic tails or loops of a number of proteins and is thought to be responsible for the direct transport of these proteins from the Golgi network to late endosomal/lysosomal structures. We have previously reported (Rodionov, Höning, Silye, Kongsvik, von Figura, Bakke, 2002.