p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway

Abstract

The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.

MAPK signaling in inflammation-associated cancer development

“…Another work also showed that JNK activities are dramatically increased in p38-deficient livers in LPS-induced hepatitis, although it remains unknown whether increased JNK activities contribute to apoptosis of hepatocytes (Heinrichsdorff et al, 2008). During inflammation-associated liver cancer development, increased activities of the JNK pathway were found to cause the accelerated proliferation rates of liver tumor cells lacking p38α (Hui et al, 2007a). Increased MKK7 phosphorylation was proposed to explain the hyperactivation of JNK in p38α-deficient cancer cells.…”

“…p38α-deficient MEFs proliferate faster and exhibit delayed senescence compared to control cells, due to the increased G1/S and G2/ M transitions by upregulation of cyclin D1 and inactivation of p53 activity (Hui et al, 2007a;Sun et al, 2007). Moreover, p38α is shown to be an important regulator of differentiation of various cell types.…”

“…Two recent reports using conditional p38α mice indicate that p38α suppresses inflammation-associated liver cancer development (Hui et al, 2007a;Sakurai et al, 2008). In the HCC model used in these studies, carcinogen treatment initiates a wide-range of cell death and tissue repair, similar to the acute phase of hepatitis.…”

“…High levels of cytokine produced by infiltrated inflammatory cells trigger massive hepatocyte proliferation to maintain tissue homeostasis. p38α was found to suppress proliferation of tumor cells via antagonizing of the JNK-c-Jun pathway (Hui et al, 2007a). Alternatively, it has been proposed that p38α can alleviate ROS accumulation and liver damage, thus attenuate proliferation of initial tumor cells in this inflammatory scenario (Sakurai et al, 2008).…”

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

“…[3][4][5][6] Initial experiments using mouse models of cancer showed that p38MAPK suppresses lung and liver tumour formation in vivo. 7,8 However, enhanced p38 phosphorylation also correlates with poor prognosis in some patients with breast cancer and hepatocellular carcinoma. 9,10 Similarly, overexpression or activation of p38MAPK has been reported in lymphomas, thyroid neoplasms and human lung tumours.…”