p38α -: A suppressor of cell proliferation and tumorigenesis

The mitogen-activated protein kinase (MAPK) p38 alpha is involved in numerous biological processes and is a drug target for inflammation-associated diseases. Genetic analysis in mice demonstrated that fetuses lacking p38 alpha are embryonic lethal owing to impaired placental development. The function of p38 alpha in mice after birth remained unclear until conditional alleles of p38 alpha were used. It was found that p38 alpha is essential for lung function in both neonatal and adult mice. Increased proliferation and impaired differentiation are the hallmarks of p38 alpha-deficient cells. Moreover, mice deficient in p38 alpha are prone to cancer development using carcinogen or oncogene-induced cancer models. p38 alpha can suppress cell proliferation by antagonizing the JNK/c-Jun pathway, which is an important regulator of proliferation and apoptosis. These findings suggest that therapeutic inhibition of p38 might lead to unwanted proliferation. Therefore, a combined inhibition of p38 and other pathways, such as the JNK pathway, should be considered for targeting cancer inflammation.