Science's STKE : signal transduction knowledge environment
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Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix-PAS domain transcription factor that is expressed in all metazoan organisms and is composed of HIF-1alpha and HIF-1beta subunits. Under hypoxic conditions, HIF-1 regulates the transcription of hundreds of genes in a cell type-specific manner. The HIF-1alpha subunit is regulated by O2-dependent hydroxylation of proline residue 402, 564, or both, by prolyl hydroxylase domain protein 2 (PHD2), which promotes binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation; and O2-dependent hydroxylation of asparagine residue 803 by factor inhibiting HIF-1 (FIH-1), which blocks the binding of the 300-kilodalton coactivator protein (p300) and CREB binding protein (CBP). ⋯ Hydroxylase activity is inhibited in the presence of low concentrations of O2, high concentrations of tricarboxylic acid cycle intermediates (isocitrate, oxaloacetate, succinate, or fumarate), or chelators of Fe(II). Receptor for activated C kinase 1 (RACK1) competes with heat shock protein 90 (HSP90) for binding to HIF-1alpha and mediates O2-independent ubiquitination and proteasomal degradation. A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1alpha.
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Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). ⋯ Now similar functions have been uncovered for the mammalian orthologs, the TLRs. TLRs expressed on CNS glia and neurons may recognize endogenous ligands and participate both in development and in responses associated with CNS injury.
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The forkhead family transcription factor Foxp3 is critical for the development and function of CD4(+)CD25(+) regulatory T cells (Tregs). A series of reports have begun to shed light on the precise role of Foxp3 in the regulation of the Treg transcriptome. Foxp3 can bind to specific gene elements, thereby altering transcription of target genes directly, and Foxp3 can alter the expression of genes encoding other transcription factors, thereby having an indirect effect on the transcription of target genes. Cells retaining aspects of Treg differentiation persist in the absence of Foxp3, which is suggestive of a Foxp3-independent aspect of Treg biology.
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The unfortunate ability of tumor cells to survive and expand in an uncontrolled manner has captivated the attention of clinicians and basic scientists alike. The molecular mechanisms that tumor cells use to grow are the very same pathways used in normal cell growth and differentiation. ⋯ The target genes that HIF members stimulate that are relevant to tumor growth include transcriptional activators and repressors and cytokines and growth factors, as well as their receptors. In this Perspective, findings from several recent studies are discussed in terms of their effect on the signal transducers, target genes, and tumor properties that are ultimately affected during EGFR-stimulated HIF signaling in cancer cells.
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The mammalian TRP (transient receptor potential) family consists of six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups. These subfamilies encompass 28 ion channels that function as diverse cellular sensors. All of the channels are permeable to monovalent cations, and most are also permeable to Ca(2+). ⋯ Finally, the phenotypes of TRP knockout mice and other transgenic models allow a degree of extrapolation to human diseases. We present an overview of current knowledge about the role of TRP channels in human disease and highlight some TRP "suspects" for which a role in disease can be anticipated. An understanding of the genetics of disease may lead to the development of targeted new therapies.