Zyxin, a focal adhesion molecule, contains LIM domains and shuttles between the cytoplasm and the nucleus. Nuclear zyxin promotes cardiomyocyte survival, which is mediated by nuclear-activated Akt. However, the molecular mechanism of how zyxin antagonizes apoptosis remains elusive. Here, we report that zyxin binds to acinus-S, a nuclear speckle protein inducing apoptotic chromatin condensation after cleavage by caspases, and prevents its apoptotic action, which is regulated by Akt. Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus. Interestingly, 14-3-3c, but not f isoform selectively, triggers zyxin nuclear translocation, which is Akt phosphorylation dependent. Zyxin is also a substrate of caspases, but Akt phosphorylation is unable to prevent its apoptotic cleavage. Expression of zyxin S142D, a phosphorylation mimetic mutant, diminishes acinus proteolytic cleavage and chromatin condensation; by contrast, wild-type zyxin or unphosphorylated S142A mutant fails. Thus, Akt regulates zyxin/acinus complex formation in the nucleus, contributing to suppression of apoptosis. Cell Death and Differentiation (2007) Zyxin is a phosphoprotein that accumulates with integrins at cell-substratum attachment sites. It has a proline-rich domain (PRD) at the N-terminus and multiple LIM domains in Cterminal half. The PRD region displays docking sequences for several proteins in actin assembly and organization, and SH3 domains that are found in a number of proteins in signal transduction pathways. [1][2][3][4][5][6][7] The LIM domain is a double-zincfinger motif that presents in proteins involved in the regulation of cell proliferation and differentiation. 8,9 Zyxin shuttles between the nucleus and sites of cell adhesion in fibroblasts, and is thus an excellent candidate for relaying information between these two compartments. 10 Although some of zyxin family proteins, including Trip6 and Ajuba, affect nuclear transcription, 11 no definite evidence has yet demonstrated that zyxin is implicated in this process.Acinus, predominantly located in the nucleus, induces apoptotic chromatin condensation after cleavage by caspases. 12 It is cleaved at both its N-and C-termini, generating a p17 active form (amino acids (aa) 228-335), which triggers chromatin condensation. Acinus contains a region similar to the RNA recognition motif of Drosophila splicing regulator Sxl, suggesting that it is implicated in RNA metabolism. Indeed, acinus is a component of functional splicesomes. 13 Acinus is also found in the apoptosis-and splicing-associated protein (ASAP) complex, which is comprised of SAP18, RNPS1, and distinct isoforms of acinus. Addition of the complex to in vitro splicing assays inhibits RNA processing. 14 Moreover, knockdown of acinus inhibits oligonucleosomal DNA fragmentation during apoptosis. 15 Acinus is also a component of exon junction complex (EJC), which is deposited on exon-intron junctions during pre-mRNA splicing, and stimulates gene expression at the RNA level. 16 Recently, we show that ...
In mammals, local production of tumor necrosis factor α (TNFα) inhibits growth hormone (GH)-induced IGF-I expression at tissue level and contributes to GH resistance caused by sepsis/endotoxemia and inflammation. Although the loss of GH responsiveness can be mediated by a parallel rise in SOCS expression, the signaling mechanisms for TNFα-induced SOCS expression at the hepatic level have not been characterized and the comparative aspects of the phenomenon, especially in lower vertebrates, are still unknown. Recently, type II SOCS, including SOCS1-3 and CISH, have been cloned in grass carp and shown to act as the feedback repressors for GH signaling via JAK 2 /STAT 5 pathway. To shed light on the mechanisms for TNFα-induced GH resistance in fish model, grass carp TNFα was cloned and confirmed to be a single-copy gene expressed in various tissues including the liver. In carp hepatocytes, incubation with the endotoxin LPS induced TNFα expression with parallel rises in SOCS1-3 and CISH mRNA levels. Similar to LPS, TNFα treatment could block GH-induced IGF-I/-II mRNA expression and elevate SOCS1, SOCS3, and CISH transcript levels. However, TNFα was not effective in altering SOCS2 expression. In parallel experiment, LPS blockade of IGF-I/-II signals caused by GH could be partially reverted by TNFα receptor antagonism. At hepatocyte level, TNFα induction also triggered rapid phosphorylation of IκBα, MEK 1/2 , ERK 1/2 , MKK 3/6 , P 38 MAPK , Akt, JAK 2, and STAT 1,3,5 , and TNFα-induced SOCS1, SOCS3, and CISH mRNA expression could be negated by inhibiting the IKK/NFκB, MAPK, PI3K/Akt, and JAK/STAT cascades. Our findings, as a whole, suggest that local production of TNFα may interfere with IGF-I/-II induction by GH in the carp liver by up-regulation of SOCS1, SOCS3, and CISH via IKK/NFκB, MAPK, PI3K/Akt, and JAK/STAT-dependent mechanisms, which may contribute to GH resistance induced by endotoxin in carp species.
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