| First Author | Li H | Year | 2019 |
| Journal | Cancer Res | Volume | 79 |
| Issue | 9 | Pages | 2167-2181 |
| PubMed ID | 30894371 | Mgi Jnum | J:274262 |
| Mgi Id | MGI:6296535 | Doi | 10.1158/0008-5472.CAN-18-1253 |
| Citation | Li H, et al. (2019) Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation. Cancer Res 79(9):2167-2181 |
| abstractText | Mice with a keratinocyte-restricted deletion of the actin polymerization-promoting molecule, N-WASP, display cyclic hair loss and skin inflammation. Here, we showed that these mice were also resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator, DNMT1, and increased expression of the senescence marker, p16Ink4a, in N-WASP-deficient epidermis. Moreover, primary N-WASP-null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases, G9a/GLP, and the DNA methyltransferase, DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes. SIGNIFICANCE: These findings demonstrate that N-WASP regulates p53-dependent senescence in keratinocytes in vitro and in vivo. |
