p38α: A Suppressor of Cell Proliferation and Tumorigenesis

Abstract

The mitogen-activated protein kinase (MAPK) p38! is involved in numerous biological processes and is a drug target for inflammation-associated diseases. Genetic analysis in mice demonstrated that fetuses lacking p38! are embryonic lethal owing to impaired placental development. The function of p38! in mice after birth remained unclear until conditional alleles of p38α were used. It was found that p38α is essential for lung functionin both neonatal and adult mice. Increased proliferation and impaired differentiation are the hallmarks of p38α-deficient cells. Moreover, mice deficient in p38α are prone to cancerdevelopment using carcinogen or oncogene-induced cancer models. p38α 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.