Evidence of p38γ and p38δ involvement in cell transformation processes

Abstract

The p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway is an important regulator of cell processes, whose deregulation leads to the development and progression of cancer. Defining the role of each p38MAPK family member in these processes has been difficult. To date, most studies of the p38MAPK pathways focused on function of the p38α isoform, which is widely considered to negatively regulate malignant transformation; nonetheless, few reports address the p38γ and p38δ isoforms. Here, we used embryonic fibroblasts derived from mice lacking p38γ or p38δ and show evidence that these isoforms participate in several processes involved in malignant transformation. We observed that lack of either p38γ or p38δ increased cell migration and metalloproteinase-2 secretion, whereas only p38δ deficiency impaired cell contact inhibition. In addition, lack of p38γ in K-Ras-transformed fibroblasts led to increased cell proliferation as well as tumorigenesis both in vitro and in vivo. Our results indicate that p38γ and p38δ have a role in the suppression of tumor development.

p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

“…Protein transfection in MEF and retroviral expression of macrophages were carried out as described (15,24).…”

“…p38δ-null mice show reduced susceptibility to skin carcinogenesis (14). However, studies in immortalized mouse embryonic fibroblasts and in K-Ras-transformed cells lacking p38γ or p38δ have indicated that these kinases can also inhibit tumor development (15). p38γ and p38δ are also expressed in immune cell lines and primary immune cells, and both are activated in myeloid cell lines in response to LPS (16,17).…”

Pro-Oncogenic Role of Alternative p38 Mitogen-Activated Protein Kinases p38γ and p38δ, Linking Inflammation and Cancer in Colitis-Associated Colon Cancer

“…p38g regulates oncogenic proteins involved in colorectal cancer development, such as K-Ras, which is mutated in 50% of colon cancers (24). Nonetheless, studies in immortalized mouse embryonic fibroblasts and in K-Ras-transformed cells lacking p38g or p38d indicated that these kinases can also inhibit tumor development by regulating processes associated with malignant cell transformation such as proliferation, contact inhibition and/or migration (25). These findings suggest that p38g and p38d are implicated in linking tumor promotion and/or progression and inflammation.…”

p38 MAPK Down-regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences

“…It has been recently shown that they can play a tumor suppressor role inhibiting cell migration, MMP2 secretion and tumor growth in MEFs (24). In contrast, p38␦-null mice are more resistant to skin tumor development (25) and colon cancer development is impaired in p38␥/␦-deficient mice (26).…”