Bommireddy R et al. (2007) Trends Mol Med "TGFbeta1 and Treg cells: alliance for tolerance."

Bommireddy R, Doetschman T

[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.

Gao F et al. (2014) Front Physiol "Trichinella spiralis, potential model nematode for epigenetics and its implication in metazoan parasitism."

Gao F, Wang R, Liu M

[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.

Chuang HC et al. (2019) J Biomed Sci "MAP4K3/GLK in autoimmune disease, cancer and aging."

Chuang HC, Tan TH

[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.

Ohtsuki T et al. (2007) IUBMB Life "T-armless tRNAs and elongated elongation factor Tu."

Ohtsuki T, Watanabe Y

[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.

McGhee JD (2000) Bioessays "Homologous tails? Or tales of homology?"

McGhee JD

[Bioessays, 2000]

Classical mutations at the mouse Brachyury (T) locus were discovered because they lead to shortened tails in heterozygous newborns. no tail (ntl) mutants in the zebrafish, as their name suggests, show a similar phenotype. In Drosophila, mutants in the brachyenteron (byn) gene disrupt hindgut formation. These genes all encode T-box proteins, a class of sequence-specific DNA binding proteins and transcription factors. Mutations in the C. elegans mab-9 gene cause massive defects in the male tail because of failed fate decisions in two tail progenitor cells. In a recent paper, Woollard and Hodgkin have cloned the mab-9 gene and found that it too encodes a T-box protein, similar to Brachyury in vertebrates and brachyenteron in Drosophila. The authors suggest that their results support models for an evolutionarily ancient role for these genes in hindgut formation. We will discuss this proposal and try to decide whether the gene sequences, gene interactions and gene expression patterns allow any conclusions to be made about the rear end of the ancestral metazoan.

Constantine R et al. (2012) Vision Res "Uncoordinated (UNC)119: coordinating the trafficking of myristoylated proteins."

Frederick JM, Baehr W, Gerstner CD, Zhang H, Constantine R

[Vision Res, 2012]

The mechanism by which myristoylated proteins are targeted to specific subcellular membrane compartments is poorly understood. Two novel acyl-binding proteins, UNC119A and UNC119B, have been shown recently to function as chaperones/co-factors in the transport of myristoylated G protein -subunits and src-type tyrosine kinases. UNC119 polypeptides feature an immunoglobulin-like -sandwich fold that forms a hydrophobic pocket capable of binding lauroyl (C12) and myristoyl (C14) side chains. UNC119A in rod photoreceptors facilitates the transfer of transducin subunits (T) from inner segment to outer segment membranes by forming an intermediate diffusible UNC119-T complex. Similar complexes are formed in other sensory neurons, as the G proteins ODR-3 and GPA-13 in Caenorhabditis elegans unc-119 mutants traffic inappropriately. UNC119B knockdown in IMCD3 cells prevents trafficking ofmyristoylated nephrocystin-3 (NPHP3), a protein associated with nephronophthisis, to cilia. Further, UNC119A was shown to transport myristoylated src-type tyrosine kinases to cell membranes and to affect T-cell receptor (TCR) and interleukin-5 receptor (IL-5R) activities. These interactions establish UNC119 polypeptides as novel lipid-binding chaperones with specificity for a diverse subset of myristoylated proteins.

Hirabayashi J (1999) Trends in Glycosylation "Mutations in possible glycosylation genes, sqv-3, sqv-7 and sqv-8, of C. elegans cause abnormal vulval formation."

Hirabayashi J

[Trends in Glycosylation, 1999]

Apoptosis and gastrulation are critical biological events required for normal development of multicellular animals. As a glycobiologist, you may easily imagine that both of these phenomena involve specific carbohydrate recognition, but actually it is rather difficult to prove. The nematode C. elegans seems to be an ideal model animal for such a proof, because its complete cell lineages have already been established, and more recently, the genome project for this organism has been accomplished. In addition, vulval formation which consists of invagination of epitherial cells underlying the cuticular layer into the inner tissues has been well studied. Essentially, this process is analogous to gastrulation. Recently, 8 genes names sqv-1-8 have been identified as those involved in normal vulval formation by a representative C. elegans genetic group [Herman, T., Hartwieg, E., and Horvitz, R. (1999) Proc. Natl. Acad. Sci. USA, 96, 968-973]. To our surprise, it turned out that three of the (sqv-3,7,8) were quite similar to the known mammalian genes encoding glucuronyltransferase, galactose transferase, and sugar nucleotide transporter [Herman, T., and Horvitz, R. (1999) Proc. Natl. Acad. Sci. US 96, 974-979].

Chitwood DJ et al. (1991) Lipids "Metabolism of plant sterols by nematodes."

Chitwood DJ, Lusby WR

[Lipids, 1991]

Parasitic nematodes do not biosynthesize sterols de novo and therefore possess a nutritional requirement for sterol, which must be obtained from their hosts. Consequently, the metabolism of phytosterols by plant-parasitic nematodes is an important process with potential for selective exploitation. The sterol compositions of several species of plant-parasitic nematodes were determined by capillary gas chromatography-mass spectrometry and compared with the sterol compositions of their hosts. Saturation of the phytosterol nucleus was the major metabolic transformation performed by the root-knot nematodes Meloidogyne arenaria and M. incognita and the corn root lesion nematode, Pratylenchus agilis. In addition to saturation, the corn cyst nematode, Heterodera zeae, dealkylated its host sterols at C-24. Because free-living nematodes can be cultured in sterol-defined artificial medium, they have been successfully used as model organisms for investigation of sterol metabolism in plant-parasitic nematodes. Major pathways of phytosterol metabolism in Caenorhabditis elegans, Turbatrix aceti and Panagrellus redivivus included C-24 dealkylation and 4 alpha-methylation (a pathway unique to nematodes). C. elegans and T. aceti introduced double bonds at C-7, and T. aceti and P. redivivus saturated the sterol nucleus similarly to the plant-parasitic species examined. Several azasteroids and long-chain dimethylalkylamines inhibited growth and development of C. elegans and also the delta 24-sterol reductase enzyme system involved in the nematode C-24 dealkylation pathway.

Kagoshima H et al. (2007) J Cell Biochem "RUNX regulates stem cell proliferation and differentiation: insights from studies of C. elegans."

Kohara Y, Kagoshima H, Shigesada K

[J Cell Biochem, 2007]

The RUNX genes encode conserved transcription factors that play vital roles in the development of various animals and human diseases. Recent studies by a few groups including ours have demonstrated that this gene family, as represented by a single ortholog designeated rnt-1, also occurs and plays intriguing roles in the simple model organism, Caenorhabditis elegans. Our genetic and molecular analyses revealed that rnt-1 is allelic to mab-2, which had previously been known to cause an abnormal development of the male tail. rnt-1 was further shown to be predominantly expressed in the stem cell-like lateral seam hypodermal cells. These cells are characterized by their abilities to undergo stem cell-like asymmetric divisions giving rise to self-renewing seam cells and various differentiated descendants of hypodermal and neuronal fates. We found that rnt-1 mutants exhibit an impaired asymmetry in the division of T cells, the posterior-most member of the seam cells. Mutant analysis indicated that rnt-1 is involved in regulating T blast cell polarity in cooperation with the Wnt signaling pathway. On the other hand, Nimmo et al. independently discovered that rnt-1 acts as a rate limiting regulator of cell proliferation in the seam cells, V1-6. In this review, we will outline these new findings and discuss their general implications in the mechanism of coordination between proliferation and differentiation of stem cells. J. Cell. Biochem. (c) 2007 Wiley-Liss, Inc.

Ravindranath AJ et al. (2016) Cancers (Basel) "The Role of the C-Clamp in Wnt-Related Colorectal Cancers."

Cadigan KM, Ravindranath AJ

[Cancers (Basel), 2016]

T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed.