Gumienny TL et al. (2013) WormBook "TGF- signaling in C. elegans."

Savage-Dunn C, Gumienny TL

[WormBook, 2013]

Transforming Growth Factor- (TGF-) superfamily ligands regulate many aspects of cell identity, function, and survival in multicellular animals. Genes encoding five TGF- family members are present in the genome of C. elegans. Two of the ligands, DBL-1 and DAF-7, signal through a canonical receptor-Smad signaling pathway; while a third ligand, UNC-129, interacts with a noncanonical signaling pathway. No function has yet been associated with the remaining two ligands. Here we summarize these signaling pathways and their biological functions.

Baker JC et al. (1997) Curr Opin Genet Dev "From receptor to nucleus: the Smad pathway."

Harland RM, Baker JC

[Curr Opin Genet Dev, 1997]

The transforming growth factor-beta (TGF-beta) superfamily plays a central role in the specification and patterning of cells in the early embryo. Several years ago, the TGF-betas were shown to signal through serine/threonine receptor kinases. Now, with the identification of Smad proteins, we can trace the TGF-beta signal transduction pathway from the receptors into the nucleus.

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

Doetschman T, Bommireddy R

[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.

Zimmerman CM et al. (2000) Gene "Transforming growth factor beta signaling mediators and modulators."

Zimmerman CM, Padgett RW

[Gene, 2000]

Transforming growth factor beta is a multi-functional growth and differentiation factor responsible for regulating many diverse biological processes in both vertebrate and invertebrate species. Among the most dramatic of TGF beta's effects are those associated with specification of cell fates during development and inhibition of cell cycle progression. The core TGF beta signaling pathway has now been described using a synergistic combination of genetic and biochemical approaches. Transmembrane receptors with intrinsic protein serine kinase activity bind ligand in the extracellular milieu and then phosphorylate intracellular proteins known as Smads. Phosphorylated Smads form heterooligomers and translocate into the nucleus where they can modulate transcriptional responses. More recent studies indicate that many other proteins serve as modulators of Smad activity, and ultimately define specific cellular responses to TGF beta. Here we describe both the simplistic core TGF beta signaling pathway and the growing number of proteins that impinge on this pathway at the level of Smad function to either enhance or inhibit TGF beta responses.

Savage-Dunn C (2001) Cytokine Growth Factor Rev "Targets of TGF beta-related signaling in Caenorhabditis elegans."

Savage-Dunn C

[Cytokine Growth Factor Rev, 2001]

With the characterization of the Smads 5 years ago, it became possible to trace the TGFB signal transduction pathway from the plasma membrane to the nucleus. Since that time, many Smad interaction partners, cofactors and target genes have been identified using a variety of experimental approaches and model systems. Understanding how these generate tissue specificity and crosstalk between pathways is an ongoing puruit for the field of TGFB signal transduction. The nematode Caenorhabditis elegans provides a simple, genetically tractable model organism in which to address this goal. This review will examine progress towards the identification of cellular and molecular targets of TGFB-related signaling in C. elegans.

Padgett RW et al. (1998) Bioessays "TGF-beta signaling, Smads, and tumor suppressors."

Das P, Krishna S, Padgett RW

[Bioessays, 1998]

The transforming growth factor-beta (TGF-beta) superfamily is used throughout animal development for regulating the growth and patterning of many tissue types. During the past few years, rapid progress has been made in deciphering how TGF-beta signals are transduced from outside the cell to the nucleus. This progress is based on biochemical studies in vertebrate systems and a combination of genetic studies in Drosophila and Caenorhabditis elegans. These studies have identified a novel family of signaling proteins, the Smad family. Smads can act positively and be phosphorylated by TGF-beta-like receptors or can act negatively and prevent activation of the positively acting group. The positively acting Smads translocate to the nucleus, bind DNA, and act as transcriptional activators. Thus, genetic and biochemical studies suggest a very simple signaling pathway, in which Smads are the primary downstream participant.

Branicky R et al. (2000) Bioessays "clk-1, mitochondria, and physiological rates."

Hekimi S, Benard C, Branicky R

[Bioessays, 2000]

Mutations in the C. elegans maternal-effect gene clk-1 are highly pleiotropic, affecting the duration of diverse developmental and behavioral processes. They result in an average slowing of embryonic and post-embryonic development, adult rhythmic behaviors, reproduction, and aging.(1) CLK-1 is a highly conserved mitochondrial protein,(2,3) but even severe clk-1 mutations affect mitochondrial respiration only slightly.(3) Here, we review the evidence supporting the regulatory role of clk-1 in physiological timing. We also discuss possible models for the action of CLK-1, in particular, one proposing that CLK-1 is involved in the coordination of mitochondrial and nuclear function. BioEssays 22:48-56, 2000.

Ji YJ et al. (2005) J Cell Biochem "RNT-1 regulation in C. elegans."

Ji YJ, Singaravelu G, Ahnn J

[J Cell Biochem, 2005]

RUNXs are important transcription factors, which are involved in animal development and human carcinogenesis. RNT-1, the only homologue of RUNXs, in Caenorhabditis elegans (C. elegans) has been identified and viable mutant animals of rnt-1 gene have been isolated and characterized recently. Genetic analyses using rnt-1 mutants have shown that RNT-1 is regulated by TGFbeta- and Wnt-signaling pathways in the body size regulation and male tail development. Here, we review our current understanding of RNT-1 functions in these signaling pathways. Furthermore, future prospects of RNT-1 and BRO-1 studies in C. elegans are discussed in this review. (c) 2005 Wiley-Liss, Inc.

Passananti C et al. (2007) Biochem Cell Biol "Che-1/AATF, a multivalent adaptor connecting transcriptional regulation, checkpoint control, and apoptosis."

Floridi A, Passananti C, Fanciulli M

[Biochem Cell Biol, 2007]

Che-1/AATF (Che-1) was originally characterized as an interacting protein for RNA polymerase II. In addition to transcriptional regulation, the evidence suggests that Che-1 has a viral factor-like S phase promoting role in counteracting Rb repression to facilitate E2F-dependent transactivation during G1-S transition. Recently, Che-1 was found to play an important role in the DNA damage response and cell-cycle checkpoint control. Genetic studies in mice revealed that Che-1 is essential for preimplantation development and the establishment of embryonic gene expression. Importantly, several findings showed that Che-1 participates in inhibiting apoptotic process. Thus, Che-1 emerges as an important adaptor that connects transcriptional regulation, cell-cycle progression, checkpoint control, and apoptosis.

Yoshida H (2003) Cell Struct Funct "The role of Apaf-1 in programmed cell death: from worm to tumor."

Yoshida H

[Cell Struct Funct, 2003]

Apoptosis or programmed cell death is an important process to eliminate unnecessary or hazardous cells. Apaf-1, a mammalian homologue of CED-4 of C. elegans, is the essential adaptor molecule in the mitochondrial pathway of apoptosis. Mice lacking Apaf-1 show accumulation of neurons in the developing central nervous system due to reduced apoptosis. Apaf-1-deficient cells are remarkably resistant to various apoptotic stimuli. Apaf-1-mediated apoptosis plays a role in the prevention of tumorigenesis. However, Apaf-1-independent cell death pathways are also indicated. In this review, we will summarize what has been learned about the role of Apaf-1 by biochemical and genetical approaches.