The Skp2 promoter integrates signaling through the NF-kappaB, p53, and Akt/GSK3beta pathways to regulate autophagy and apoptosis

Abstract

NF-kappaB and p53 are important regulators of the cellular response to stress. Here, we identify the Skp2 gene as being both an NF-kappaB and p53 target after DNA damage. However, Skp2 expression can be either induced or repressed in a manner requiring both the p52 NF-kappaB subunit and p53, with subsequent effects on autophagy, apoptosis, and p53 function. This process is regulated by the Akt(PKB)/GSK3beta pathway. When Akt is active, GSK3beta is repressed, allowing p52 and p53 to cooperatively induce Skp2 expression. However, if Akt is inactive, GSK3beta phosphorylates p52 at Ser 222. This modification disrupts p52 homodimer/Bcl-3 complexes and facilitates transcriptional repression by p52/-c-Rel. The Skp2 promoter therefore integrates signaling through the NF-kappaB, p53, and Akt/GSK3beta pathways to regulate cell fate in response to DNA damage.