p27 (Kip1) role as a transcriptional regulator

p27, also called Kip1, is a well known protein with a crucial role in cell cycle progression and cancer. p27 best known function is the inhibition of cyclin-dependent kinase (cdk) activities, cyclin E-CDK2 and cyclin D-CDK4 complexes, and has a role in controlling the cell cycle progression at G1. However it was unclear if p27 may have other roles in the nucleus other than acting as a CDK inhibitor.

paper published this week in Oncogene shows that p27 has also a role as a transcriptional repressor, which is independent of cyclin-cdk regulation. This work has been leaded by Oriol Bachs and Raffy Pippa from IDIBAPS, and we, Gunes and myself, and other researchers from IMIMCIEMAT and University of Toulouse have participated in the project.

Model illustrating the participation of p27 on the organization of p130/E2F4 repressor complexes. p130 first drives E2F4 to the promoters, then p27 is subsequently loaded by directly interacting by its carboxyl-domain with both p130 and E2F4. Finally, p27 recruits the co-repressors HDAC1 and mSIN3A on these promoters.

Analysis of Chip-on-chip data for p27 allowed us to identify specific regulatory targets of this protein, together with gene expression analysis in p27-deficient and p27-mutated MEFS, we were able to show that p27 works mostly as a transcriptional represor. Furthermore, this work shows that p27 interacts directly with p130/E2F4 at the promoter of target genes and that this new function of p27 could have a role in the major aggressiveness of tumors with low levels of p27.

We are very glad we had the opportunity to participate in this exiting project, and we are proud that two of the methods developed in our lab, Gitools and IntOGen, were important to generate the results of this project. We also used Onexus, another tool under development in the lab, to create a supplementary web (http://bg.upf.edu/p27) to browse the data generated for this project.

Follow this link to read the full paper: