Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Targets of rapamycin (TORs) are conserved phosphatidylinositol kinase-related kinases that are involved in the coordination between nutritional or mitogenic signals and cell growth. Here we report the initial characterization of two Schizosaccharomyces pombe TOR homologs, tor1(+) and tor2(+). tor2(+) is an essential gene, whereas tor1(+) is required only under starvation and other stress conditions. Specifically, Deltator1 cells fail to enter stationary phase or undergo sexual development and are sensitive to cold, osmotic stress, and oxidative stress. In complex with the prolyl isomerase FKBP12, the drug rapamycin binds a conserved domain in TORs, FRB, thus inhibiting some of the functions of TORs. Mutations at a conserved serine within the FRB domain of Saccharomyces cerevisiae TOR proteins led to rapamycin resistance but did not otherwise affect the functions of the proteins. The S. pombe tor1(+) exhibits different features; substitution of the conserved serine residue, Ser(1834), with arginine compromises its functions and has no effect on the inhibition that rapamycin exerts on sexual development in S. pombe.
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PMID:The fission yeast TOR homolog, tor1+, is required for the response to starvation and other stresses via a conserved serine. 1109 19

The TOR proteins are known as key regulators of cell growth in response to nutritional and mitogenic signals and as targets for the immunosuppressive and anti-cancerous drug rapamycin. The fission yeast Schizosaccharomyces pombe has two TOR homologues, tor1+ and tor2+. Despite their structural similarity, these genes have distinct functions: tor1+ is required under starvation, extreme temperatures, and osmotic or oxidative stress conditions, whereas tor2+ is required under normal growth conditions. Surprisingly, rapamycin does not seem to inhibit the S. pombe TOR-related functions. Rapamycin specifically inhibits sexual development in S. pombe, and this seems to stem from direct inhibition of the S. pombe FKBP12 homologue. Why S. pombe cells are resistant to rapamycin during the growth phase is as yet unclear and awaits further analysis of the TOR-dependent signaling pathways.
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PMID:The fission yeast TOR proteins and the rapamycin response: an unexpected tale. 1456 Sep 53

TOR protein kinases are key regulators of cell growth in eukaryotes. TOR is also known as the target protein for the immunosuppressive and potentially anticancer drug rapamycin. The fission yeast Schizosaccharomyces pombe has two TOR homologs. tor1+ is required under starvation and a variety of stresses, while tor2+ is an essential gene. Surprisingly, to date no rapamycin-sensitive TOR-dependent function has been identified in S. pombe. Herein, we show that S. pombe auxotrophs, in particular leucine auxotrophs, are sensitive to rapamycin. This sensitivity is suppressed by deletion of the S. pombe FKBP12 or by introducing a rapamycin-binding defective tor1 allele, suggesting that rapamycin inhibits a tor1p-dependent function. Sensitivity of leucine auxotrophs to rapamycin is observed when ammonia is used as the nitrogen source and can be suppressed by its replacement with proline. Consistently, using radioactive labeled leucine, we show that cells treated with rapamycin or disrupted for tor1+ are defective in leucine uptake when the nitrogen source is ammonia but not proline. Recently, it has been reported that tsc1+ and tsc2+, the S. pombe homologs for the mammalian TSC1 and TSC2, are also defective in leucine uptake. TSC1 and TSC2 may antagonize TOR signaling in mammalian cells and Drosophila. We show that reduction of leucine uptake in tor1 mutants is correlated with decreased expression of three putative amino acid permeases that are also downregulated in tsc1 or tsc2. These findings suggest a possible mechanism for regulation of leucine uptake by tor1p and indicate that tor1p, as well as tsc1p and tsc2p, positively regulates leucine uptake in S. pombe.
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PMID:Regulation of leucine uptake by tor1+ in Schizosaccharomyces pombe is sensitive to rapamycin. 1546 17

We show here that similar to starvation, ingestion of the bacterial product rapamycin (RAP) interferes with egg production in female Drosophila. RAP ingestion results in posterior follicle cells (PFC) in stage 8/9 egg chambers losing epithelial polarity, after which PFC invade and phagocytose the oocyte. Nurse cell apoptosis then occurs, followed by total egg chamber destruction. Knockdown of the RAP receptor FKBP12 specifically in PFC rescues oogenesis and also the laying of embryos that develop into normal offspring in flies fed RAP. Thus, somatic cells can be induced to destroy intact oocytes without a requirement for earlier oocyte compromise. Genes that control apicobasal epithelial polarity were found to be involved in egg chamber destruction. In flies bearing heterozygous mutations for discs large, merlin, or warts, PFC epithelia fail to lose polarity on RAP treatment. Embryo laying and offspring development to adulthood are rescued in all of these mutants when housed on RAP concentrations that block oogenesis in wild-type flies. The response to RAP was found to be conserved in mammals, as mouse ovarian follicles cultured in vitro with RAP show the rapid destruction of the oocyte by adjacent granulosa cells. Inducible somatic oocyte destruction is thus implicated in controlling egg survival in insects and mammals.
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PMID:Inducible somatic oocyte destruction in response to rapamycin requires wild-type regulation of follicle cell epithelial polarity. 2044 42

Target of rapamycin (TOR) kinases are key regulators of cell growth, proliferation, and structure in eukaryotes, processes that are highly coordinated during the infectious cycle of eukaryotic pathogens. Database mining revealed three TOR kinases in the trypanosomatid parasite Leishmania major, as defined by homology to the phosphoinositide 3-kinase-related kinase (PIKK) family and a signature conserved FKBP12/rapamycin-binding domain. Consistent with the essential roles of TOR complexes in other organisms, we were unable to generate null TOR1 or TOR2 mutants in cultured L. major promastigotes. In contrast, tor3(-) null mutants were readily obtained; while exhibiting somewhat slower growth, tor3(-) maintained normal morphology, rapamycin sensitivity, and differentiation into the animal-infective metacyclic stage. Significantly, tor3(-) mutants were unable to survive or replicate in macrophages in vitro, or to induce pathology or establish infections in mice in vivo. The loss of virulence was associated with a defect in acidocalcisome formation, as this unique organelle was grossly altered in tor3- mutants and no longer accumulated polyphosphates. Correspondingly, tor3- mutants showed defects in osmoregulation and were sensitive to starvation for glucose but not amino acids, glucose being a limiting nutrient in the parasitophorous vacuole. Thus, in Leishmania, the TOR kinase family has expanded to encompass a unique role in AC function and biology, one that is essential for parasite survival in the mammalian infective stage. Given their important roles in cell survival and virulence, inhibition of TOR kinase function in trypanosomatids offers an attractive target for chemotherapy.
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PMID:Expansion of the target of rapamycin (TOR) kinase family and function in Leishmania shows that TOR3 is required for acidocalcisome biogenesis and animal infectivity. 2055 Dec 25

A great deal of evolutionary conservation has been found in the control of oocyte development, from invertebrates to women. However, little is known of mechanisms that control oocyte loss over time. Oocyte loss is often assumed to be a result of oocyte-intrinsic deficiencies or damage. In fruit flies, starvation results in halted oocyte production by germline stem cells and induces oocyte loss midway through development. When we fed wild-type flies the bacterial compound Rapamycin (RAP) to mimic starvation, production of new oocytes continued, but mid-stage loss sterilized the animals. Surprisingly, follicle cell invasion and phagocytosis of the oocyte preceded any signs of germ cell death. RAP-induced egg chamber loss was prevented when RAP receptor FKBP12 was knocked down specifically in follicle cells. Oogenesis continued past the mid-stages, and these mutants continued to lay embryos that could develop into normal adults. Hence, intact healthy oocytes can be destroyed by somatic cells responding to extrinsic stimuli. We termed this process inducible somatic oocyte destruction. RAP treatment of mouse follicles in vitro resulted in phagocytic uptake of the oocyte by granulosa cells as seen in flies. We hypothesize that extrinsic modes of oocyte loss occur in mammals.
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PMID:Intrinsic and extrinsic mechanisms of oocyte loss. 2065 Oct 35