E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation (ENVIADO AUN NO ACEPTADO)

ABEL L. CARCAGNO; MARIELA C. MARAZITA; MARÍA F. OGARA; JULIETA M. CERUTI; SILVINA V. SONZOGNI; MARÍA E. SCASSA; LUCIANA E. GIONO; EDUARDO T. CÁNEPA

MOLECULAR CELL

CELL PRESS

Lugar: Cambridge; Año: 2010

1097-2765

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 mRNA and protein levels oscillate periodically, accumulating during late G1 and S phases. Here, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. This regulation is responsible for p19INK4d oscillatory behavior. 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 stimulated cell proliferation and increased the fraction of cells in S phase. 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.