Phosphorylation of transcriptional regulators in the retinoblastoma protein pathway by UL97, the viral cyclin-dependent kinase encoded by human cytomegalovirus

摘要

Abstract Human cytomegalovirus (HCMV) encodes a viral cyclin-dependent kinase (v-CDK), the UL97 protein. UL97 phosphorylates Rb, p107 and p130, thereby inactivating all three retinoblastoma (Rb) family members. Rb proteins function through regulating the activity of transcription factors to which they bind. Therefore, we examined whether the UL97-mediated regulation of the Rb tumor suppressors also extended to their binding partners. We observed that UL97 phosphorylates LIN52, a component of p107- and p130-assembled transcriptionally repressive DREAM complexes that control transcription during the G0/G1 phases, and the Rb-associated E2F3 protein that activates transcription through G1 and S phases. Intriguingly, we also identified FoxM1B, a transcriptional regulator during the S and G2 phases, as a UL97 substrate. This survey extends the influence of UL97 beyond simply the Rb proteins themselves to their binding partners, as well as past the G1/S transition into later stages of the cell cycle. Highlights ? HCMV v-CDK UL97 phosphorylates multiple cell cycle substrates. ? DREAM complex assembly likely driven in part by UL97-mediated phosphorylation. ? Cancer relevant E2F3 mutation impairs phosphorylation by UL97 and cellular CDKs. ? G2 substrate FoxM1 targeted by UL97.