The mitogen-activated protein kinase (MAPK) cascades, in which the major components are MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK), are conserved eukaryotic signaling pathways (2, 7, 14, 46). The general function of the MAPK cascades is to link a variety of extracellular stimuli to nuclear responses, i.e., the modulation of gene expression (45). MAPK is activated by dual phosphorylation on threonine and tyrosine residues catalyzed by MAPKK, and MAPKK is activated by serine/threonine phosphorylation catalyzed by MAPKKK. In mammals, at least three MAPK cascades have been identified. The MAPKs in each pathway are ERK (extracellular signal-regulated kinase), JNK/SAPK (cJun N-terminal kinase/stress-activated protein kinase), and p38. The ERK cascade is mostly responsive to mitogenic and differentiation stimuli, whereas the JNK and p38 cascades are strongly activated by proinflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-␣), and extracellular stresses, such as UV irradiation and osmotic shock (4,23,29,36).In the ERK cascade, Raf (Raf-1, A-Raf, and B-Raf), MEK (MEK1 and MEK2), and ERK (ERK1 and ERK2) correspond to MAPKKK, MAPKK, and MAPK, respectively (36). The p38 cascade contains p38␣/CSBP/RK/Mxi2 (12,25,37,56) and p38␤ (18) as MAPKs and MKK3 (9) and MKK6 (6,13,32,35,42) as MAPKKs, while in the JNK cascade the MAPKs are JNK1, JNK2, and JNK3 (also known as SAPK␥, SAPK␣, and SAPK␤, respectively) (8,11,19,22,31), and the MAPKKs are SEK1/MKK4/JNKK1 (9,26, 38) and MKK7/JNKK2 (33,44,48). The specificity of the MAPKKKs involved in the JNK and p38 cascades is less clear. For instance, the TAK1 (52), ASK1 (16), and MLK3 (43) MAPKKKs can activate both the JNK and p38 cascades, while the MEKK1 (28, 50, 53) and MEKK4 (10) MAPKKKs selectively activate the JNK cascade.The identification of numerous components of the MAPK cascades as described above suggests that there are a number of these distinct signaling pathways in cells. Furthermore, studies of JNK3-deficient mice (54) indicate the existence of a JNK3-specific cascade that cannot be complemented by the other JNK family members, even though JNK1, JNK2, and JNK3 exhibit over 80% identity, and these JNKs seem to be

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The SHC1 gene encodes a signaling and transforming protein that has been implicated in the aging process in worms and mammals. In this study we examined 230 Japanese centenarians and 180 healthy younger controls and looked at the SHC1 locus as a candidate region that may be associated with longevity. We identified 12 single nucleotide polymorphisms (SNPs) within a 10-kb region encompassing the entire SHC1 gene from the DNA of 30 centenarians and 24 healthy younger controls. Five SNPs, including three nonsynonymous sites, lay within coding elements, six were located within introns, and one was in the 3' untranslated region. All of these SNPs were relatively rare, with a minor allele frequency of less than 5% in our subjects. A pairwise linkage disequilibrium analysis using the r2 statistic showed that two of the SNP pairs are in tight linkage disequilibrium at this locus. We investigated the possible association of SHC1 with longevity using association analyses with allelotypes and haplotypes but found that the SNPs identified in SHC1 had no impact on longevity for Japanese centenarians.