| First Author | Raghavan A | Year | 2012 |
| Journal | Am J Respir Cell Mol Biol | Volume | 46 |
| Issue | 4 | Pages | 431-6 |
| PubMed ID | 22033266 | Mgi Jnum | J:196040 |
| Mgi Id | MGI:5486431 | Doi | 10.1165/rcmb.2011-0128OC |
| Citation | Raghavan A, et al. (2012) Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1. Am J Respir Cell Mol Biol 46(4):431-6 |
| abstractText | Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. Here, we report for the first time, to the best of our knowledge, a novel function of FoxM1 in the hypoxia-stimulated proliferation of human pulmonary artery smooth muscle cells (HPASMCs). Exposure to hypoxia caused a marked up-regulation of FoxM1 gene expression, mainly at the transcription level, and this induction correlated with HPASMC cell proliferation. The knockdown of FoxM1 inhibited the hypoxia-stimulated proliferation of HPASMCs. We found that the knockdown of HIF-2alpha, but not HIF-1alpha, diminished FoxM1 induction in response to hypoxia. However, the knockdown of FoxM1 did not alter expression levels of HIF-2alpha or HIF-1alpha, suggesting that HIF-2alpha is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2alpha-dependent pathway, thereby promoting HPASMC proliferation. |
