Critical Role for FoxO3a-Dependent Regulation of p21 ^CIP1/WAF1 in Response to Statin Signaling in Cardiac Myocytes

Abstract

Abstract-Statins are widely used clinical drugs that exert beneficial growth-suppressive effects in patients with cardiac hypertrophy. We investigated the role of the cell cycle inhibitor p21 CIP1/WAF1 (p21) in statin-dependent inhibition of hypertrophic growth in postmitotic cardiomyocytes. We demonstrate that lovastatin fails to inhibit cardiac hypertrophy to angiotensin II in p21 Ϫ/Ϫ mice and that reconstitution of p21 function by TAT.p21 protein transduction can rescue statin action in these otherwise normally developed animals. Lovastatin specifically recruits the forkhead box FoxO3a transcription factor to the p21 promoter, mediating transcriptional transactivation of the p21 gene as analyzed in isolated primary cardiomyocytes. Lovastatin also stimulates protein kinase B/Akt kinase activity, and Akt-dependent phosphorylation forces p21 in the cytoplasm, where it inhibits Rho-kinases contributing to the suppression of cardiomyocyte hypertrophy. Loss of p21 or FoxO3a by RNA interference causes a general inhibition of lovastatin signal transduction. These results suggest that p21 functions as FoxO3a downstream target to mediate an statin-derived anti-hypertrophic response. Taken together, our genetic and biochemical data delineate an essential function of p21 for statin-dependent inhibition of cardiac myocyte hypertrophy. (Circ Res. 2007;100:50-60.)

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

“…It functions as a tumor suppressor by regulating many genes that control diverse biological activities, including cell proliferation (Dijkers et al, 2000;Hauck et al, 2007) and apoptosis (Sunters et al, 2003;Li et al, 2007). In this study, we found that overexpression of FoxO3a induced, while silencing of FoxO3a decreased, CCNG2 promoter activity.…”

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

“…23) p21 has a wide specificity for substrates such as CDK4/6, CDK2, and Cdc2, leading to cell cycle arrest at multiple phases. 22 27,[32][33][34] Because ANP gene expression is mediated by the transcription factor GATA-4 and signaling pathways leading to cardiomyocyte hypertrophy activate GATA-4 under various hypertrophic conditions, 35,36) upregulation of ANP gene expression suggests activation of a signaling pathway leading to the development of hypertrophy. It is possible that H 2 O 2 activated the hypertrophic signaling pathway in H9c2 cells even in the presence of BAPTA-AM.…”

FoxO3a and disease progression

“…FoxO3a activation increases cell cycle inhibitor proteins p21 and p27, both of which subsequently suppress G1 to S cell cycle transition [51][52][53][54] . Although p27 is transcriptionally regulated by FoxO3a via the PI3K/Aktdependent axis, it has been shown that p27 is also regulated via the FoxO3a/NF-κB/c-Myc-dependent pathway.…”