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The p38 MAP kinase pathway plays important roles in the response to many types of environmental stresses as well as in the processes of inflammation and apoptosis, although sometimes may have other functions unrelated to stress, such as the regulation of cell proliferation, differentiation and motility in particular cell types.There are four p38 MAP kinases (p38α, p38β, p38γ and p38δ) that are encoded by different genes.The p38 MAP kinase family member that is expressed ubiquitiously and at higher levels is p38α, and most of the published literature on p38 MAP kinases actually refers to p38α.We are investigating the implication ofp38α in tumorigenesis and found that this signaling protein can suppress tumor formation at different levels.For example, p38α plays an important role in the contact inhibition response, the cell cycle arrest induced by cell-ceil contacts.This involves upregulation of the cell cycle inhibitor p27Kipl via the p38α-mediated inhibition of EGFR signaling.Interfering with this regulatory mechanism leads to higher cellular densities and facilitates oncogenic transformation.In addition, p38α can trigger apoptosis in cells with tumorigenic potential by detecting the intracellular accumulation of reactive oxygen species (ROS) induced by oncogenes.However, p38α appears to have different roles at later stages of the tumorigenic process.Thus, established human cancer cell lines have developed mechanisms to interfere with the apoptotic effect of p38α in response to ROS, which results in the accumulation of high levels of oxidative stress and enhanced tumorigenicity.Interestingly, cancer cells with high ROS levels (due to p38α downregulation) appear to be hyper-sensitized to apoptosis induced by cytotoxic agents.The activity of p38α has been also correlated with the enhanced malignancy of certain types of human tumors, in contrast with the negative role of this signaling pathway in cancer initiation.We will discuss the mechanisms by which p38α may contribute to human cancer progression.Finally, we are using genetically modified mice to investigate the functions of p38α in vivo and have obtained evidence indicating that p38α may play different roles depending on the tissues and types of cancer.