p27^Kip1and p21^Cip1collaborate in the regulation of transcription by recruiting cyclin–Cdk complexes on the promoters of target genes

Abstract

Transcriptional repressor complexes containing p130 and E2F4 regulate the expression of genes involved in DNA replication. During the G1 phase of the cell cycle, sequential phosphorylation of p130 by cyclin-dependent kinases (Cdks) disrupts these complexes allowing gene expression. The Cdk inhibitor and tumor suppressor p27Kip1 associates with p130 and E2F4 by its carboxyl domain on the promoters of target genes but its role in the regulation of transcription remains unclear. We report here that p27Kip1 recruits cyclin D2/D3–Cdk4 complexes on the promoters by its amino terminal domain in early and mid G1. In cells lacking p27Kip1, cyclin D2/D3–Cdk4 did not associate to the promoters and phosphorylation of p130 and transcription of target genes was increased. In late G1, these complexes were substituted by p21Cip1-cyclin D1–Cdk2. In p21Cip1 null cells cyclin D1–Cdk2 were not found on the promoters and transcription was elevated. In p21/p27 double null cells transcription was higher than in control cells and single knock out cells. Thus, our results clarify the role of p27Kip1 and p21Cip1 in transcriptional regulation of genes repressed by p130/E2F4 complexes in which p27Kip1 and p21Cip1 play a sequential role by recruiting and regulating the activity of specific cyclin–Cdk complexes on the promoters.

p27Kip1 represses the Pitx2-mediated expression of p21Cip1 and regulates DNA replication during cell cycle progression

“…Interestingly, it has been recently reported that p27 and p21 collaborate in the G 1 transcriptional regulation of genes necessary for DNA replication by recruiting different cyclinCdk complexes on the promoters of these genes. 30 Thus, p21 appears as a central regulator of Cdk2 activity at mid-late G 1 and that the fine modulation of p21 levels is crucial for progression of cells through G 1 phase. The relevance of the amount of p21 on cell cycle progression has also been emphasized in a recent article showing that the decision at the end of mitosis to either start the next cell cycle or to enter a transient G 0 -like state depends on p21 levels.…”

Halofuginone and artemisinin synergistically arrest cancer cells at the G1/G0 phase by upregulating p21Cip1 and p27Kip1

“…Hence, CDK2 inhibitors are potentially effective anticancer agents [30]. p21 Cip1 and p27 Kip1 are two main CDK-inhibitors (CKIs); they regulate CDK2 activity by binding to cyclin-CDK complexes thereby inhibiting their catalytic activity [31]. Thus, the regulation of CDK2 through p27 Kip1 and p21 Cip1 plays a key role in controlling the tempo of gene transcription in G1 phase and in the subsequent progression to the cell division [32].…”

Mechanisms associated to apoptosis of cancer cells by phenolic extracts from two canned common beans varieties (Phaseolus vulgarisL.)

“…These proteins play an important role in regulating the proliferation, apoptosis, and differentiation (Yang et al, ). Several authors have pointed out that accumulation of p21 inhibits the cyclin–Cdk complex necessary for the G1 to S‐phase and for the G2 to M‐phase transitions (Orlando et al, ).…”

“…Several authors have pointed out that accumulation of p21 inhibits the cyclin-Cdk complex necessary for the G1 to S-phase and for the G2 to M-phase transitions (Orlando et al, 2015).…”