[PDF][PDF] Cell cycle regulation by p38 MAP kinases

C Ambrosino, AR Nebreda - Biology of the Cell, 2001 - academia.edu
Biology of the Cell, 2001academia.edu
MAP kinases are signaling intermediaries that allow eukaryotic cells to interpret and
respond to many different stimuli. Three major MAP kinase pathways have been identified.
These include the extracellular signal-regulated kinases (ERK1 and ERK2), which are
mainly activated by mitogens and serum stimulation. In contrast, the c-Jun N-terminal
kinases (JNK) and the p38 MAP kinases are strongly activated by environmental and
genotoxic stresses. The p38 MAP kinases are also implicated in several aspects of the …
MAP kinases are signaling intermediaries that allow eukaryotic cells to interpret and respond to many different stimuli. Three major MAP kinase pathways have been identified. These include the extracellular signal-regulated kinases (ERK1 and ERK2), which are mainly activated by mitogens and serum stimulation. In contrast, the c-Jun N-terminal kinases (JNK) and the p38 MAP kinases are strongly activated by environmental and genotoxic stresses. The p38 MAP kinases are also implicated in several aspects of the immune response. The first member of this family to be isolated was a protein (p38), which was rapidly phosphorylated on tyrosine residues upon lipopolysaccharide stimulation (Han et al., 1994). It was also found as an stress-activated protein kinase (Reactivating Kinase or RK) that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock protein Hsp27 (Rouse et al., 1994). Finally, the same protein was identified as a target of pyridinylimidazole drugs (Cytokine-Suppressive antiinflammatory drug Binding Protein or CSBP) that inhibit the production of the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor (Lee et al., 1994). Analysis of the cDNA sequence revealed that this protein (p38/RK/CSBP) was the vertebrate homologue of the Saccharomyces cerevisiae protein kinase Hog1. Other p38 isoforms were subsequently cloned and named p38, p38γ and p38δ or SAPK2b, SAPK3 and SAPK4, respectively (Jiang et al., 1996, Lechner et al., 1996; Mertens et al., 1996; Goedert et al., 1997; Jiang et al., 1997; Enslen et al., 1998). These four p38 MAP kinase isoforms are 57-73% identical in their amino acid sequences but differ in their expression patterns and sensitivities to chemical inhibitors such as SB203580 and SB202190, which only interacts with p38α and p38 (reviewed by Cohen, 1997). In addition, the p38 MAP kinase isoforms are activated with differential specificity by the MAP kinase kinases MKK3, MKK4 and MKK6 (Enslen et al., 1998; Alonso et al., 2000) and they also have differential substrate specificities, albeit with some overlap (reviewed by Cohen, 1997).
The p38 MAP kinase pathway has been traditionally associated with the stress and immune response and more recently with the regulation of apoptosis and some differentiation processes (reviewed by Nebreda and Porras, 2000). Here we will focus on the emergent role of p38 MAP kinases (p38α and p38, unless otherwise indicated) in the regulation of cell proliferation and cell cycle checkpoints (figure 1).
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