3 research outputs found
Mechanisms of MEOX1 and MEOX2 Regulation of the Cyclin Dependent Kinase Inhibitors p21CIP1/WAF1 and p16INK4a in Vascular Endothelial Cells
Senescence, the state of permanent cell cycle arrest, has been associated
with endothelial cell dysfunction and atherosclerosis. The cyclin dependent
kinase inhibitors p21CIP1/WAF1 and p16INK4a govern the
G1/S cell cycle checkpoint and are essential for determining whether
a cell enters into an arrested state. The homeodomain transcription factor
MEOX2 is an important regulator of vascular cell proliferation and is a direct
transcriptional activator of both p21CIP1/WAF1 and p16INK4a.
MEOX1 and MEOX2 have been shown to be partially functionally redundant during
development, suggesting that they regulate similar target genes in
vivo. We compared the ability of MEOX1 and MEOX2 to activate p21CIP1/WAF1
and p16INK4a expression and induce endothelial cell cycle arrest.
Our results demonstrate for the first time that MEOX1 regulates the MEOX2
target genes p21CIP1/WAF1 and p16INK4a. In addition,
increased expression of either of the MEOX homeodomain transcription factors
leads to cell cycle arrest and endothelial cell senescence. Furthermore, we
show that the mechanism of transcriptional activation of these cyclin dependent
kinase inhibitor genes by MEOX1 and MEOX2 is distinct. MEOX1 and MEOX2 activate
p16INK4a in a DNA binding dependent manner, whereas they induce
p21CIP1/WAF1 in a DNA binding independent manner