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M O Hengartner

Publications and source records attributed to M O Hengartner.

At least 19 recordsLinked to original sources
PubMed2006

miRNAs and apoptosis: RNAs to die for.

MicroRNAs (miRNAs) are small non-coding RNAs of about 18-24 nucleotides in length that negatively regulate gene expression. Discovered only recently, it has become clear that they are involved in many biological processes such as developmental timing, differentiation and cell death. Data that connect miRNAs to various kinds of diseases, particularly cancer, are accumulating. miRNAs can influence cancer development in many ways, including the regulation of cell proliferation, cell transformation, and cell death. In this review, we focus on miRNAs that have been shown to play a role in the regulation of apoptosis. We first describe in detail how Drosophila has been utilized as a model organism to connect several miRNAs with the cell death machinery. We discuss the genetic approaches that led to the identification of those miRNAs and subsequent work that helped to establish their function. In the second part of the review article, we focus on the involvement of miRNAs in apoptosis regulation in mammals. Intriguingly, many of the miRNAs that regulate apoptosis have been shown to affect cancer development. In the end, we discuss a virally encoded miRNA that influences the cell death response in the mammalian host cell. In summary, the data gathered over the recent years clearly show the potential and important role of miRNAs to regulate apoptosis at various levels and in several organisms.

Animals↗
PubMed2004

Death and more: DNA damage response pathways in the nematode C. elegans.

Genotoxic stress is a threat to our cells' genome integrity. Failure to repair DNA lesions properly after the induction of cell proliferation arrest can lead to mutations or large-scale genomic instability. Because such changes may have tumorigenic potential, damaged cells are often eliminated via apoptosis. Loss of this apoptotic response is actually one of the hallmarks of cancer. Towards the effort to elucidate the DNA damage-induced signaling steps leading to these biological events, an easily accessible model system is required, where the acquired knowledge can reveal the mechanisms underlying more complex organisms. Accumulating evidence coming from studies in Caenorhabditis elegans point to its usefulness as such. In the worm's germline, DNA damage can induce both cell cycle arrest and apoptosis, two responses that are spatially separated. The latter is a tightly controlled process that is genetically indistinguishable from developmental programmed cell death. Upstream of the central death machinery, components of the DNA damage signaling cascade lie and act either as sensors of the lesion or as transducers of the initial signal detected. This review summarizes the findings of several studies that specify the elements of the DNA damage-induced responses, as components of the cell cycle control machinery, the repairing process or the apoptotic outcome. The validity of C. elegans as a tool to further dissect the complex signaling network of these responses and the high potential for it to reveal important links to cancer and other genetic abnormalities are addressed.

Animals↗
PubMed2004

Genome-wide RNAi identifies p53-dependent and -independent regulators of germ cell apoptosis in C. elegans.

We used genome-wide RNA interference (RNAi) to identify genes that affect apoptosis in the C. elegans germ line. RNAi-mediated knockdown of 21 genes caused a moderate to strong increase in germ cell death. Genetic epistasis studies with these RNAi candidates showed that a large subset (16/21) requires p53 to activate germ cell apoptosis. Apoptosis following knockdown of the genes in the p53-dependent class also depended on a functional DNA damage response pathway, suggesting that these genes might function in DNA repair or to maintain genome integrity. As apoptotic pathways are conserved, orthologues of the worm germline apoptosis genes presented here could be involved in the maintenance of genomic stability, p53 activation, and fertility in mammals.

Animals↗
PubMed2001

C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.

BACKGROUND: In response to genotoxic stress, cells activate checkpoint pathways that lead to a transient cell cycle arrest that allows for DNA repair or to apoptosis, which triggers the demise of genetically damaged cells. RESULTS: During positional cloning of the C. elegans rad-5 DNA damage checkpoint gene, we found, surprisingly, that rad-5(mn159) is allelic with clk-2(qm37), a mutant previously implicated in regulation of biological rhythms and life span. However, clk-2(qm37) is the only C. elegans clock mutant that is defective for the DNA damage checkpoint. We show that rad-5/clk-2 acts in a pathway that partially overlaps with the conserved C. elegans mrt-2/S. cerevisiae RAD17/S. pombe rad1(+) checkpoint pathway. In addition, rad-5/clk-2 also regulates the S phase replication checkpoint in C. elegans. Positional cloning reveals that the RAD-5/CLK-2 DNA damage checkpoint protein is homologous to S. cerevisiae Tel2p, an essential DNA binding protein that regulates telomere length in yeast. However, the partial loss-of-function C. elegans rad-5(mn159) and clk-2(qm37) checkpoint mutations have little effect on telomere length, and analysis of the partial loss-of-function of S. cerevisiae tel2-1 mutant failed to reveal typical DNA damage checkpoint defects. CONCLUSIONS: Using C. elegans genetics we define the novel DNA damage checkpoint protein RAD-5/CLK-2, which may play a role in oncogenesis. Given that Tel2p has been shown to bind to a variety of nucleic acid structures in vitro, we speculate that the RAD-5/CLK-2 checkpoint protein may act at sites of DNA damage, either as a sensor of DNA damage or to aid in the repair of damaged DNA.

Adenosine Triphosphatases↗
PubMed2001

CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.

The C. elegans genes ced-2, ced-5, and ced-10, and their mammalian homologs crkII, dock180, and rac1, mediate cytoskeletal rearrangements during phagocytosis of apoptotic cells and cell motility. Here, we describe an additional member of this signaling pathway, ced-12, and its mammalian homologs, elmo1 and elmo2. In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations. In mammalian cells, ELMO1 functionally cooperates with CrkII and Dock180 to promote phagocytosis and cell shape changes. CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements. These studies identify CED-12/ELMO as an upstream regulator of Rac1 that affects engulfment and cell migration from C. elegans to mammals.

Adaptor Proteins, Signal Transducing↗
PubMed2001

jkk-1 and mek-1 regulate body movement coordination and response to heavy metals through jnk-1 in Caenorhabditis elegans.

Although in vitro evidence suggests two c-Jun N-terminal kinase (JNK) kinases, MKK4 and MKK7, transactivate JNK, in vivo confirmation is incomplete. In fact, JNK deficiency may differ from the composite deficiency of MKK4 and MKK7 in Drosophila and mice. Recently, the Caenorhabditis elegans homolog of human JNK, jnk-1, and two MKK-7s, mek-1 and jkk-1, were cloned. Here we characterize jnk-1, which encodes two isoforms JNK-1 alpha and JNK-1 beta. A null allele, jnk-1(gk7), yielded worms with defective body movement coordination and modest mechanosensory deficits. Similarly to jkk-1 mutants, elimination of GABAergic signals suppressed the jnk-1(gk7) locomotion defect. Like mek-1 nulls, jnk-1(gk7) showed copper and cadmium hypersensitivity. Conditional expression of JNK-1 isoforms rescued these defects, suggesting that they are not due to developmental errors. While jkk-1 or mek-1 inactivation mimicked jnk-1(gk7) locomotion and heavy metal stress defects, respectively, mkk-4 inactivation did not, but rather yielded defective egg laying. Our results delineate at least two different JNK pathways through jkk-1 and mek-1 in C.elegans, and define interaction between MKK7, but not MKK4, and JNK.

Alternative Splicing↗
PubMed2001

Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans.

Genetic studies have identified over a dozen genes that function in programmed cell death (apoptosis) in the nematode Caenorhabditis elegans. Although the ultimate effects on cell survival or engulfment of mutations in each cell death gene have been extensively described, much less is known about how these mutations affect the kinetics of death and engulfment, or the interactions between these two processes. We have used four-dimensional-Nomarski time-lapse video microscopy to follow in detail how cell death genes regulate the extent and kinetics of apoptotic cell death and removal in the early C. elegans embryo. Here we show that blocking engulfment enhances cell survival when cells are subjected to weak pro-apoptotic signals. Thus, genes that mediate corpse removal can also function to actively kill cells.

ATP-Binding Cassette Transporters↗
PubMed2001

Calcium dynamics during fertilization in C. elegans.

BACKGROUND: Of the animals typically used to study fertilization-induced calcium dynamics, none is as accessible to genetics and molecular biology as the model organism Caenorhabditis elegans. Motivated by the experimental possibilities inherent in using such a well-established model organism, we have characterized fertilization-induced calcium dynamics in C. elegans. RESULTS: Owing to the transparency of the nematode, we have been able to study the calcium signal in C. elegans fertilization in vivo by monitoring the fluorescence of calcium indicator dyes that we introduce into the cytosol of oocytes. In C. elegans, fertilization induces a single calcium transient that is initiated soon after oocyte entry into the spermatheca, the compartment that contains sperm. Therefore, it is likely that the calcium transient is initiated by contact with sperm. This calcium elevation spreads throughout the oocyte, and decays monotonically after which the cytosolic calcium concentration returns to that preceding fertilization. Only this single calcium transient is observed. CONCLUSION: Development of a technique to study fertilization induced calcium transients opens several experimental possibilities, e.g., identification of the signaling events intervening sperm binding and calcium elevation, identifying the possible roles of the calcium elevation such as the completion of meiosis, the formation of the eggshell, and the establishing of the embryo's axis of symmetry.

Animals↗
PubMed2001

Programmed cell death: alive and well in the new millennium.

Research performed over the past decade has transformed apoptosis from a distinctive form of cell death known only by its characteristic morphology and genomic destruction to an increasingly well understood cellular disassembly pathway remarkable for its complex and multifaceted regulation. Here, we summarize current understanding of apoptotic events, note recent advances in this field and identify questions that might help guide research in the coming years.

Animals↗
PubMed2001

How the worm removes corpses: the nematode C. elegans as a model system to study engulfment.

Apoptotic cell death in the nematode C. elegans culminates with the removal of the dying cells from the organism. This removal is brought forth through a rapid and specific engulfment of the doomed cell by one of its neighbors. Over half a dozen genes have been identified that function in this process in the worm. Many of these engulfment genes have functional homologs in Drosophila and higher vertebrates. Indeed, there is growing evidence supporting the hypothesis that the pathways that mediate the removal of apoptotic cells might be, at least in part, conserved through evolution.

Animals↗
PubMed2000

The biochemistry of apoptosis.

Apoptosis--the regulated destruction of a cell--is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

Animals↗
PubMed2000

A conserved checkpoint pathway mediates DNA damage--induced apoptosis and cell cycle arrest in C. elegans.

To maintain genomic stability following DNA damage, multicellular organisms activate checkpoints that induce cell cycle arrest or apoptosis. Here we show that genotoxic stress blocks cell proliferation and induces apoptosis of germ cells in the nematode C. elegans. Accumulation of recombination intermediates similarly leads to the demise of affected cells. Checkpoint-induced apoptosis is mediated by the core apoptotic machinery (CED-9/CED-4/CED-3) but is genetically distinct from somatic cell death and physiological germ cell death. Mutations in three genes--mrt-2, which encodes the C. elegans homolog of the S. pombe rad1 checkpoint gene, rad-5, and him-7-block both DNA damage-induced apoptosis and cell proliferation arrest. Our results implicate rad1 homologs in DNA damage-induced apoptosis in animals.

Animals↗
PubMed2000

A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans.

Similar to mammalian excitotoxic cell death, necrotic-like cell death (NCD) in Caenorhabditis elegans can be initiated by hyperactive ion channels. Here we investigate the requirements for genes that execute and regulate programmed cell death (PCD) in necrotic-like neuronal death caused by a toxic MEC-4 channel. Neither the kinetics of necrosis onset nor the total number of necrotic corpses generated is altered by any C. elegans mutation known to block PCD, which provides genetic evidence that the activating mechanisms for NCD and apoptotic cell death are distinct. In contrast, all previously reported ced genes required for phagocytotic removal of apoptotic corpses, as well as ced-12, a new engulfment gene we have identified, are required for efficient elimination of corpses generated by distinct necrosis-inducing stimuli. Our results show that a common set of genes acts to eliminate cell corpses irrespective of the mode of cell death, and provide the first identification of the C. elegans genes that are required for orderly removal of necrotic cells. As phagocytotic mechanisms seem to be conserved from nematodes to humans, our findings indicate that injured necrotic cells in higher organisms might also be eliminated before lysis through a controlled process of corpse removal, a hypothesis that has significant therapeutic implications.

Animals↗
PubMed1999

Human CED-6 encodes a functional homologue of the Caenorhabditis elegans engulfment protein CED-6.

The rapid engulfment of apoptotic cells is a specialized innate immune response used by organisms to remove apoptotic cells. In mammals, several receptors that recognize apoptotic cells have been identified; molecules that transduce signals from these receptors to downstream cytoskeleton molecules have not been found, however [1] [2] [3]. Our previous analysis of the engulfment gene ced-6 in Caenorhabditis elegans has suggested that CED-6 is an adaptor protein that participates in a signal transduction pathway that mediates the specific recognition and engulfment of apoptotic cells [1]. Here, we describe our isolation and characterization of a human cDNA encoding a protein, hCED-6, with strong sequence similarity to C. elegans CED-6. As is the case with the worm protein, hCED-6 contains a phosphotyrosine-binding (PTB) domain and potential Src-homology domain 3 (SH3) binding sites. Both CED-6 and hCED-6 contain a predicted coiled-coil domain in the middle region. The hCED-6 protein lacks the extended carboxyl terminus found in worm CED-6; this carboxy-terminal extension appears not to be essential for CED-6 function in C. elegans, however. Overexpression of hCED-6 rescues the engulfment defect of ced-6 mutants in C. elegans significantly, suggesting that hCED-6 is a functional homologue of C. elegans CED-6. Human ced-6 is expressed widely in most human tissues. Thus, CED-6, and the CED-6 signal transduction pathway, might be conserved from C. elegans to humans and are present in most, if not all, human tissues.

Amino Acid Sequence↗