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Trends Mol Med,
2007]
Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T(reg))-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca(2+)-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T(reg) cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T(h) IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.
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Nature,
1990]
What molecular signalling machines tell a precursor cell to develop into a specialized structure? In one case, described in three papers, including that by Aroian et al. on page 693 of this issue, these machines turn out to be a receptor tyrosine kinase and a ras protein.
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[
Curr Biol,
2000]
A second case has been found of a nematode gene involved in developmental timing that encodes a short, non-coding RNA. Both RNAs are expressed at specific times and appear to repress target genes by interacting with their 3' untranslated regions. A coincidence? Or does this pathway attract small RNA regulators?
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Front Physiol,
2014]
The recent discovery of DNA methylation in the nematode T.spiralis may raise the possibility of using it as a potential model organism for epigenetic studies instead of C. elegans, which is deficient in this important epigenetic modification. In contrast to the free-living nematode C. elegans, T. spiralis is a parasitic worm that possesses a complicated life cycle and undergoes a complex developmental regulation of genes. We emphasize that the differential methylomes in the different life-history stages of T. spiralis can provide insight on how DNA methylation is triggered and regulated. In particular, we have demonstrated that DNA methylation is involved in the regulation of its parasitism-related genes. Further computational analyses indicated that the regulatory machinery for DNA methylation can also be found in the T. spiralis genome. By a logical extension of this point, we speculate that comprehensively addressing the epigenetic machinery of T. spiralis may help to understand epigenetics in invertebrates. Furthermore, considering the implication of epigenetics in metazoan parasitism, using T. spiralis as an epigenetic model organism may further contribute to drug development against metazoan parasites.
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Methods Mol Biol,
2000]
Complete or partial embryonic cell lineages are available for several animal model systems. In the case of the nematode Caenorhabditis elegans, the entire embryonic cell lineage has been determined and is largely invariant. This makes cell lineage analysis a potentially useful tool for assessing mutant phenotypes in C. elegans. Indeed, lineage analysis of some mutants has shown that one cell can be transformed into a different cell resulting in duplication or absence of certain tissues...
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J Biomed Sci,
2019]
MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKC through phosphorylating PKC at Ser-538 residue, leading to activation of IKK/NF-B. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
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Science,
1984]
Within the past few years researchers have finally begun to be able to peer inside a hitherto impenetrable black box, namely, the development of complex organisms. The genes that control the commitment of embryonic cells to specific fates are now being found and characterized. A case in point is reported in this issue of Science (p. 409). Victor Ambros of Harvard University and H. Robert Horvitz of Massachusetts Institute of Technology have identified genes that affect the timing of developmental events in the roundworm Caenorhabditis elegans.
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Annu Rev Cell Dev Biol,
2011]
The generation of individual neuron types in the nervous system is a multistep process whose endpoint is the expression of neuron type-specific batteries of terminal differentiation genes that determine the functional properties of a neuron. This review focuses on the regulatory mechanisms that are involved in controlling the terminally differentiated state of a neuron. I review several case studies from invertebrate and vertebrate nervous systems that reveal that many terminal differentiation features of a neuron are coregulated via terminal selector transcription factors that initiate and maintain terminal differentiation programs.
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IUBMB Life,
2007]
Most tRNAs share a common secondary structure containing a T arm, a D arm, an anticodon arm and an acceptor stem. However, there are some exceptions. Most nematode mitochondrial tRNAs and some animal mitochondrial tRNAs lack the T arm, which is necessary for binding to canonical elongation factor Tu (EF-Tu). The mitochondria of the nematode Caenorhabditis elegans have a unique EF-Tu, named EF-Tu1, whose structure has supplied clues as to how truncated tRNAs can work in translation. EF-Tu1 has a C-terminal extension of about 60 aa that is absent in canonical EF-Tu. Recent data from our laboratory strongly suggests that EF-Tu1 recognizes the D-arm instead of the T arm by a mechanism involving this C-terminal region. Further biochemical analysis of mitochondrial tRNAs and EF-Tu from the distantly related nematode Trichinella spp. and sequence information on nuclear and mitochondrial DNA in arthropods suggest that T-armless tRNAs may have arisen as a result of duplication of the EF-Tu gene. These studies provide valuable insights into the co-evolution of RNA and RNA-binding proteins. IUBMB Life, 59: 68-75, 2007.
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Curr Opin Genet Dev,
1996]
Oocytes accumulate a dowry of maternal mRNAs in preparation for embryogenesis. These maternal transcripts are kept dormant until late oogenesis or early embryogenesis when their translation is activated. In recent years, three types of translational control acting on maternal mRNAs have emerged: translational activation by cytoplasmic polyadenylation, translational activation by RNA localization, and regulated translational repression. In each case, translational control depends on the binding of trans-acting factors to sequences in the 3' untranslated region (3'UTR). Identification of these trans-acting factors is beginning to shed light on the molecular mechanisms that mediate translational control.