| First Author | Xu H | Year | 2015 |
| Journal | Biochim Biophys Acta | Volume | 1853 |
| Issue | 1 | Pages | 65-73 |
| PubMed ID | 25307521 | Mgi Jnum | J:234220 |
| Mgi Id | MGI:5789502 | Doi | 10.1016/j.bbamcr.2014.10.002 |
| Citation | Xu H, et al. (2015) AMPKalpha1 deficiency promotes cellular proliferation and DNA damage via p21 reduction in mouse embryonic fibroblasts. Biochim Biophys Acta 1853(1):65-73 |
| abstractText | Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, controls the cell cycle and protects against DNA damage. However, the molecular mechanisms by which AMPKalpha isoform regulates DNA damage remain largely unknown. The aim of this study was to determine if AMPKalpha deletion contributes to cellular hyperproliferation by reducing p21(WAF1/Cip1) (p21) expression thereby leading to accumulated DNA damage. The markers for DNA damage, cell cycle proteins, and apoptosis were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKalpha1, or AMPKalpha2 homozygous deficient (AMPKalpha1(-/-), AMPKalpha2(-/-)) mice by Western blot, flow cytometry, and cellular immunofluorescence staining. Deletion of AMPKalpha1, the predominant AMPKalpha isoform, but not AMPKalpha2 in immortalized MEFs led to spontaneous DNA double-strand breaks (DSB) which corresponded to repair protein p53-binding protein 1 (53BP1) foci formation and subsequent apoptosis. Furthermore, AMPKalpha1 localizes to chromatin and AMPKalpha1 deletion down-regulates cyclin-dependent kinase inhibitor, p21, an important protein that plays a role in decreasing the incidence of spontaneous DSB via inhibition of cell proliferation. In addition, AMPKalpha1 null cells exhibited enhanced cell proliferation. Finally, p21 overexpression partially blocked the cellular hyperproliferation of AMPKalpha1-deleted MEFs via the inhibition of cyclin-dependent kinase 2 (CDK2). Taken together, our results suggest that AMPKalpha1 plays a fundamental role in controlling the cell cycle thereby affecting DNA damage and cellular apoptosis. |
