p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

Abstract

p38␣ mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38␣ knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38␣ are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38␣-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38␣ also have increased extracellular signalregulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38␣. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38␣؊/؊ cells. Thus, p38␣ seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways. INTRODUCTIONThe family of p38 mitogen-activated protein kinases (MAPKs) are strongly activated by stress and inflammatory cytokines, but nonstressful stimuli can also activate p38 MAPKs, leading to the regulation of cellular functions such as proliferation, differentiation, and survival. Four different p38 MAPK family members have been identified, p38␣, ␤, ␥, and ␦, also known as stress-activated kinase (SAPK)2a, SAPK2b, SAPK3, and SAPK4, respectively, which may have both overlapping and specific functions (reviewed by Cohen, 1997;Nebreda and Porras, 2000;Ono and Han, 2000;Kyriakis and Avruch, 2001). p38␣ is broadly expressed and is also the most abundant p38 family member present in most cell types. Targeted inactivation of the mouse p38␣ gene results in embryonic death due to a placental defect (Adams et al., 2000;Mudgett et al., 2000;Tamura et al., 2000). Studies using cell lines have suggested an important role for p38 MAPKs in the regulation of cardiomyocyte differentiation, hypertrophy, and apoptosis (Wang et al., 1998;Zechner et al., 1998;Mackay and Mochly-Rosen, 1999;Saurin et al., 2000; Stephanou et al., 2000). However, p38␣ does not seem to play a critical role in the development of the embryonic heart in mice (Adams et al., 2000), although heterozygous p38␣ϩ/Ϫ mice have been reported to be less sensitive to myocardial cell death caused by ischemia-reperfusion (Otsu et al., 2003). In addition, cardiac-specific expression of dominant negative forms of p38␣ and their activators MKK3 and MKK6 enhances cardiac hypertrophy in transgenic mice and/or makes the mice resistant to cardiac fibrosis (Braz et al., 2003;Zhang et al., 2003b).The role of p38 MAPKs in apoptosis depends on the cell type and the stimuli (reviewed by Nebreda and Porras, 2000). Most of the d...

UV‐induced interaction between p38 MAPK and p53 serves as a molecular switch in determining cell fate

“…It was shown that p38-or p53-deficient cells were more sensitive to both LUV and HUV-induced apoptosis than wild-type cells, suggesting they are essential for the cellular endurance to stresses, no matter mild or intensive, and cells lacking either of them are more susceptible to apoptosis. The cellular protective effects of p38 and p53 which have been previously reported, may be due to their functions in cell cycle arrest and DNA repair [9,22,23]. Remarkable differences between LUV and HUV-induced cell responses were observed.…”

“…p38 is not only reported to be phosphorylated and activated to mediate cell apoptosis [7][8][9], but also to have cell protective effects under certain circumstances [10,11]. Why p38 has opposing functions in determining cell fate in different situations remains unclear.…”

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

“…These phosphorylation events activate p53 to execute growth inhibition and apoptosis programs. It has been shown that mouse embryonic fibroblasts (MEFs) derived from MAPK14 knockout mice (p38-MAPKa À/À ) are more resistant to apoptosis induced by several stimuli (49), which correlated well with decreased expression of p53-regulated proapoptotic genes.…”

Procaspase 8 and Bax Are Up-regulated by Distinct Pathways in Streptococcal Pyrogenic Exotoxin B-induced Apoptosis

“…ERK inhibits Fas-induced tumor cell apoptosis (17), whereas JNKs and p38 MAPK are involved in the pro-apoptotic signal pathways, e.g. the JNK-dependent pathway mediates TNF-␣-induced apoptosis (18), and p38␣ MAPK seems to sensitize cells to apoptosis by up-regulating Bax (19).…”