Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-cycle entry is critical for homeostatic control in physiologic response of higher organisms but is not well understood. The antibody response begins with induction of naive mature B cells, which are naturally arrested in G(0)/G(1) phase of the cell cycle, to enter the cell cycle in response to antigen and cytokine. BLyS (BAFF), a cytokine essential for mature B cell development and survival, is thought to act mainly by attenuation of apoptosis. Here, we show that BLyS alone induces cell-cycle entry and early G(1) cell-cycle progression, but not S-phase entry, in opposition to the cyclin-dependent kinase inhibitors p18(INK4c). Independent of its survival function, BLyS enhances the synthesis of cyclin D2, in part through activation of NF-kappaB, as well as CDK4 and retinoblastoma protein phosphorylation. By convergent activation of the same cell-cycle regulators in opposition to p18(INK4c), B cell receptor signaling induces cell-cycle entry and G(1) progression in synergy with BLyS, but also DNA replication. The failure of BLyS to induce S-phase cell-cycle entry lies in its inability to increase cyclin E and reduce p27(Kip1) expression. Antagonistic cell-cycle regulation by BLyS and p18(INK4c) is functionally linked to apoptotic control and conserved from B cell activation in vitro to antibody response in vivo, further indicating a physiologic role in homeostasis.
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PMID:Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1. 1559 44

A proliferation inducing ligand (APRIL) and B cell activating factor belonging to the TNF family (BAFF/BLyS) have been implicated in IgA class switch recombination in thymus-independent (TI) B cell responses. Dendritic cells (DC) are thought to regulate Ig class switching in TI B cell responses by providing B cells with cytokines, including APRIL and BAFF. We therefore set out to analyze the regulation of APRIL and BAFF expression by human monocyte-derived DC (moDC). We observed that moDC produce and secrete APRIL, but could not detect expression of BAFF. Importantly, stimulation with the Toll-like receptor ligands CpG and poly I:C specifically induced APRIL production, while other Toll-like receptor ligands were ineffective. The increase in APRIL was dependent on translation, but surprisingly not transcription. Instead, enhanced APRIL production and secretion resulted from activation of protein kinase receptor (PKR), as it was completely inhibited by the specific inhibitor of PKR, 2-aminopurine. This suggests that the specific induction of APRIL by CpG and poly I:C, and the signal integration by PKR, are regulated by translational modification and hint at a role for APRIL in the TI B cell response to viral infections.
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PMID:Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner. 1789 38