INVESTIGADORES
CERUTI Julieta Maria
artículos
Título:
E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation.
Autor/es:
CARCAGNO AL; MARAZITA, M; OGARA, MF; CERUTI, JM; SONZOGNI, SV; SCASSA, MARÍA; GIONO, LE; CÁNEPA E T
Revista:
PLOS ONE
Editorial:
PUBLIC LIBRARY SCIENCE
Referencias:
Lugar: San Francisco; Año: 2011 vol. 6 p. 1 - 13
ISSN:
1932-6203
Resumen:
Background: A central aspect of development and disease is the control of cell proliferation through regulation of the
mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators
whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a
unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the
directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under
normal conditions, a feature reminiscent of cyclins.A central aspect of development and disease is the control of cell proliferation through regulation of the
mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators
whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a
unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the
directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under
normal conditions, a feature reminiscent of cyclins.
Methodology/Principal Findings: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1
through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and
restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19
periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating
the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway
using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased
the fraction of cells in S phase.In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1
through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and
restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19
periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating
the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway
using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased
the fraction of cells in S phase.
Conclusions/Significance: The results described here support a model of normal cell cycle progression in which, following
phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle
driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes,
bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the
G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional
mechanism to limit E2F activity.The results described here support a model of normal cell cycle progression in which, following
phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle
driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes,
bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the
G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional
mechanism to limit E2F activity.