Figure 9.

Hypothetic scheme of cell death induction pathway triggered roscovitine and CR8 in human neuroblastoma (NB) cells. In growing NB cells, the cell survival/cell death balance is maintained by the Bcl-2 family member Mcl-1, a survival factor that binds to and neutralizes proapoptotic proteins such as Noxa. Mcl-1 is a short-lived protein being constantly synthesized (through RNA polymerase 2, itself under the control of CDK7/cyclin H and CDK9/cyclin T) and constantly degraded (through the Mcl-1 ubiquitin ligase [MULE] and the proteasome). The CDK inhibitors roscovitine and CR8 interact with CDK7 and CDK9, preventing phosphorylation of RNA polymerase 2 at Ser-2 and Ser-9, respectively. Consequently, mRNA synthesis is inhibited. Short-lived mRNAs and short-lived proteins are down-regulated. This is the case for Mcl-1. Reduction of Mcl-1 protein level results in a transient increase in free Noxa protein, which triggers apoptotic cell death through a Bax/Bak-dependent pathway. Although p53 may be up-regulated, it is not involved in Mcl-1 down-regulation and cell death.