Abstract
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.
Highlights
The G1/S cell cycle checkpoint is critical for determining whether a cell will enter into S phase and replicate its genome, or enter into an arrested state and delay cellular proliferation [1]
We show that MEOX1 and Mesenchyme homeobox 2 (MEOX2) activation of p16INK4a gene is dependent upon DNA binding whereas their activation of p21CIP1/WAF1 gene transcription is via a DNA binding independent mechanism
Our results demonstrate for the first time that MEOX1 regulates the MEOX2 target genes p21CIP1/WAF1 and p16INK4a
Summary
The G1/S cell cycle checkpoint is critical for determining whether a cell will enter into S phase and replicate its genome, or enter into an arrested state and delay cellular proliferation [1]. This state of arrest can be either temporary (quiescence) or it can be permanent (senescence) [1]. Senescence is associated with aging and is thought to contribute to atherosclerotic vascular disease [6,7]. Senescent endothelial cells have reduced nitric oxide synthase expression [11,12,13] and altered metabolism, which results in endothelial dysfunction and contributes to the progression of vascular diseases, such as atherosclerosis [6,7]
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