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P21 as a transcriptional co-repressor of S-phase and mitotic control genes

Abstract: It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes.

 Authorship: Ferrándiz N., Caraballo J.M., García-Gutierrez L., Devgan V., Rodriguez-Paredes M., Lafita M.C., Bretones G., Quintanilla A., Muñoz-Alonso M.J., Blanco R., Reyes J.C., Agell N., Delgado M.D., Dotto G.P., León J.,

 Fuente: PLoS One, 2012, 7(5), e37759

 Publisher: Public Library of Science

 Publication date: 01/05/2012

 No. of pages: 13

 Publication type: Article

 DOI: 10.1371/journal.pone.0037759

 ISSN: 1932-6203

 Spanish project: SAF08-01581

 Publication Url: https://doi.org/10.1371/journal.pone.0037759

Authorship

NURIA FERRANDIZ DIAZ

JUAN MANUEL CARABALLO OTERO

LUCIA GARCIA GUTIERREZ

DEVGAN, VIKRAM

RODRIGUEZ-PAREDES, MANUEL

MARIA DEL CARMEN LAFITA NAVARRO

GABRIEL BRETONES SANCHEZ

ANDREA QUINTANILLA CAVIA

MARIA JOSE MUÑOZ ALONSO

REYES, JOSE C.

AGELL, NEUS