Sensitivity of human carcinoma cell lines to a cytotoxic cell penetrant mimetic of p21

摘要

It has been suggested that disrupting proliferating cell nuclear(PCNA)can lead to apoptosis and indicates an avenue for potential therapies that may overcome the problems caused by resistance to current chemotherapeutic agents.PCNA is a 36kDa trimer involved in DNA replication and repair.PCNA is believed to regulate many protein-protein interactions by acting as molecular scaffolding for the proteins involved.Such interactions are thought to occur via a PCNA interacting protein(PIP)box,with the consensus sequence(QXX(I/L/M)XX(F/H/D)(F/Y).For example,PCNA interacts with polymerase delta,the MSH2/MSH6 DNA mismatch repair complex and also the cyclin dependent kinase(CDK)inhibitor,p21.It is the interaction between p21 and PCNA that is of particular interest for the disruption of PCNA function in this study.The p21 carboxy-terminal domain interacts with the interdomain connector loop of PCNA,which is believed to prevent the interaction between polymerase delta and PCNA and therefore blocks replication.It is probable that p21 can block mismatch repair functions in a similar way.It has been suggested that small analogs mimicking p21 action may disrupt PCNA function.This study demonstrates the cytotoxicity of a cell penetrating mimetic of p21 when used to treat human carcinoma cell lines.