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P21WAF1 represses cell cycle genes in K562 cells acting as a transcriptional modulator

AuthorsFerrándiz, Nuria ; León, Javier
Issue Date2012
CitationEACR 22 (2012)
Abstract[Introduction]: p21 CIP1 (p21 herein after) is a member of the Cip/Kip family of inhibitors of cell cycle progression. The first discovered p21 function and so far its best studied biochemical activity was the inhibition of cyclin-dependent kinases. However, other studies have shown that p21 has other functions such as inhibition apoptosis induced by DNA-damaging agents and induction of senescence or differentiation. Besides, p21 has been implicated in the control of transcription by direct association and modulation of transcription factors. Nonetheless, there is litlle inlormation on the biological significance of p21- dependent regulation of gene expression and to what extent it is linked to effects on the cell cycle. To investigate the roles of p21 in transcriptional we studied the gene expression changes using a human leukernia cell line (K562) with inducible p21 expression (Kp21). [Materials and Methods]: Kp21 gene expression profile was performed by using an Affymetrix HG-U133A chip. Protein and mRNA expression were measured by Western-blot and RT-qPCR respectively. Chromatin immunoprecipitation (ChiP) assays were performed to study the p21 and CDK2 binding to the transcription start site of cell cycle genes. [Results]: 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 rapidly 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. Moreover, Chip assays indicated that p21 was bound to human CCNE2 gene in the vicinity of the transcription start site. p21 was also lound on the promoter of other three down-regulated genes but not in control genes not regulalated by p21. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. [Conclusions]: p21 exerts a repressive effect on a relevant number of genes controlling cell cycle. 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.
DescriptionTrabajo presentado al "22th Biennial Congress of the European Association for Cancer Research" celebrado en Barcelona del 7 al 10 de julio de 2012.-- et al.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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