共查询到20条相似文献,搜索用时 15 毫秒
1.
《Autophagy》2013,9(6):597-599
Dietary restriction extends life span in diverse species including Canorhabditis elegans. However, the downstream cellular targets regulated by dietary restriction are largely unknown. Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span. Since autophagy and longevity control are highly conserved from C. elegans to mammals, a similar role for autophagy in dietary restriction-mediated life span extension may also exist in mammals. 相似文献
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In Caenorhabditis elegans, the insulin/IGF pathway participates in the decision to initiate dauer development. Dauer is a diapause stage that is triggered by environmental stresses, such as a lack of nutrients. Insulin/IGF receptor mutants arrest constitutively in dauer, an effect that can be suppressed by mutations in other elements of the insulin/IGF pathway or by a reduction in the activity of the nuclear hormone receptor daf‐12. We have isolated a pkc‐1 mutant that acts as a novel suppressor of the dauer phenotypes caused by insulin/IGF receptor mutations. Interactions between insulin/IGF mutants and the pkc‐1 suppressor mutant are similar to those described for daf‐12 or the DAF‐12 coregulator din‐1. Moreover, we show that the expression of the DAF‐12 target daf‐9, which is normally elevated upon a reduction in insulin/IGF receptor activity, is suppressed in a pkc‐1 mutant background, suggesting that pkc‐1 could link the daf‐12 and insulin/IGF pathways. pkc‐1 has been implicated in the regulation of peptide neurosecretion in C. elegans. Although we demonstrate that pkc‐1 expression in the nervous system regulates dauer formation, our results suggest that the requirement for pkc‐1 in neurosecretion is independent of its role in modulating insulin/IGF signalling. pkc‐1 belongs to the novel protein kinase C (nPKC) family, members of which have been implicated in insulin resistance and diabetes in mammals, suggesting a conserved role for pkc‐1 in the regulation of the insulin/IGF pathway. 相似文献
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Aging and insulin signaling differentially control normal and tumorous germline stem cells 下载免费PDF全文
Shih‐Han Kao Chen‐Yuan Tseng Chih‐Ling Wan Yu‐Han Su Chang‐Che Hsieh Haiwei Pi Hwei‐Jan Hsu 《Aging cell》2015,14(1):25-34
Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age‐dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC–male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging. 相似文献
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The TOR (Target of Rapamycin) protein kinase pathway plays a central role in sensing and responding to nutrients, stress,
and intracellular energy state. TOR complex 1 (TORC1) is comprised of TOR, Raptor, and Lst8 and its activity is sensitive
to inhibition by the macrolide antibiotic rapamycin. TORC1 regulates protein synthesis, ribosome biogenesis, autophagy, and
ultimately cell growth through the phosphorylation of S6 K, 4E-BP, and other substrates. As TORC1 activity is positively or
negatively modulated in response to upstream regulators, cellular growth rate is, respectively, enhanced or suppressed. A
separate multiprotein TOR complex, TORC2, is insensitive to direct inhibition by rapamycin and does not regulate growth patterns
directly; TORC2 can, however, impact certain aspects of TORC1 signaling and cell survival. TOR signaling is an ancient pathway,
conserved among the yeasts, Dictyostelium, C. elegans, Drosophila, mammals, and Arabidopsis. This review will focus on the regulation of TORC1 in mammalian cells in the context of amino acid sensing/regulation and
intracellular ATP homeostasis, but will also include comparisons among other organisms. 相似文献
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Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans'' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15–20 day adulthood. All of the known mutations and treatments that extend C. elegans'' reproductive period also regulate longevity, suggesting that reproductive span is normally linked to life span. C. elegans has two canonical TGF-ß signaling pathways. We recently found that the TGF-ß Dauer pathway regulates longevity through the Insulin/IGF-1 Signaling (IIS) pathway; here we show that this pathway has a moderate effect on reproductive span. By contrast, TGF-ß Sma/Mab signaling mutants exhibit a substantially extended reproductive period, more than doubling reproductive span in some cases. Sma/Mab mutations extend reproductive span disproportionately to life span and act independently of known regulators of somatic aging, such as Insulin/IGF-1 Signaling and Dietary Restriction. This is the first discovery of a pathway that regulates reproductive span independently of longevity and the first identification of the TGF-ß Sma/Mab pathway as a regulator of reproductive aging. Our results suggest that longevity and reproductive span regulation can be uncoupled, although they appear to normally be linked through regulatory pathways. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(8):1001-1003
The pathway of apoptosis is conserved in the three model species: mammals, Drosophila, and C. elegans. The apoptotic protease-activating factor 1, an essential protein conserved in all three species, is responsible for the activation of the initiator caspase-9 in mammalian cells. The structure of the auto-inhibited form of Apaf-1 reveals a critical role for ADP, which serves as an organizing center for four adjoining domains. The ADP-binding pocket contains features that are important for designing other nucleotide analogs. ATP binding is a pre-requisite for the formation of the apoptosome. Despite strong sequence conservation between Apaf-1 and its orthologues in Drosophila and C. elegans, it is unclear whether they employ similar mechanisms for their own activation and for activating caspases. Much of the underlying mechanisms remain to be investigated by structural biology and biochemistry. 相似文献
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Neganova I Al-Qassab H Heffron H Selman C Choudhury AI Lingard SJ Diakonov I Patterson M Ghatei M Bloom SR Franks S Huhtaniemi I Hardy K Withers DJ 《Biology of reproduction》2007,76(6):1045-1053
Insulin receptor signaling regulates female reproductive function acting in the central nervous system and ovary. Female mice that globally lack insulin receptor substrate (IRS) 2, which is a key mediator of insulin receptor action, are infertile with defects in hypothalamic and ovarian functions. To unravel the tissue-specific roles of IRS2, we examined reproductive function in female mice that lack Irs2 only in the neurons. Surprisingly, these animals had minimal defects in pituitary and ovarian hormone levels, ovarian anatomy and function, and breeding performance, which indicates that the central nervous system IRS2 is not an obligatory signaling component for the regulation of reproductive function. Therefore, we undertook a detailed analysis of ovarian function in a novel Irs2 global null mouse line. Comparative morphometric analysis showed reduced follicle size, increased numbers of atretic follicles, as well as impaired oocyte growth and antral cavity development in Irs2 null ovaries. Granulosa cell proliferation was also defective in the Irs2 null ovaries. Furthermore, the insulin- and eCG-stimulated phosphoinositide-3-OH kinase signaling events, which included phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3-beta, were impaired, whereas mitogen-activated protein kinase signaling was preserved in Irs2 null ovaries. These abnormalities were associated with reduced expression of cyclin D2 and increased CDKN1B levels, which indicates dysregulation of key components of the cell cycle apparatus implicated in ovarian function. Our data suggest that ovarian rather than central nervous system IRS2 signaling is important in the regulation of female reproductive function. 相似文献
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Morton DB 《Molecular neurobiology》2004,29(2):97-115
Invertebrate model systems have a long history of generating new insights into neuronal signaling systems. This review focuses
on cyclic GMP signaling and describes recent advances in understanding the properties and functions of guanylyl cyclases in
invertebrates. The sequencing of three invertebrate genomes has provided a complete catalog of the guanylyl cyclases in C. elegans, Drosophila, and the mosquito Anopheles gambiae. Using this data and that from cloned guanylyl cyclases in Manduca sexta, C. elegans, and Drosophila, plus predictions and models from vertebrate guanylyl cyclases, evidence is presented that there is a much broader array
of properties for these enzymes than previously realized. In addition to the classic homodimeric receptor guanylyl cyclases,
C. elegans has at least two receptor guanylyl cyclases that are predicted to require heterodimer formation for activity. Soluble guanylyl
cyclases are generally recognized as being obligate heterodimers that are activated by nitric oxide (NO). Some of the soluble
guanylyl cyclases in C. elegans may heterodimeric, but all appear to be insensitive to NO. The β2 soluble guanylyl cyclase subunit in mammals and similar
ones in Manduca and Drosophila are active in the absence of additional subunits and there is evidence that Drosophila and Anopheles also express an additional subunit that enhances this activity. 相似文献
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Urko del Castillo Megan M. Gnazzo Christopher G. Sorensen Turpin Ken C. Q. Nguyen Emily Semaya Yuwan Lam Matthew A. de Cruz Joshua N. Bembenek David H. Hall Blake Riggs Vladimir I. Gelfand Ahna R. Skop 《Traffic (Copenhagen, Denmark)》2019,20(6):436-447
Ataxin‐2, a conserved RNA‐binding protein, is implicated in the late‐onset neurodegenerative disease Spinocerebellar ataxia type‐2 (SCA2). SCA2 is characterized by shrunken dendritic arbors and torpedo‐like axons within the Purkinje neurons of the cerebellum. Torpedo‐like axons have been described to contain displaced endoplasmic reticulum (ER) in the periphery of the cell; however, the role of Ataxin‐2 in mediating ER function in SCA2 is unclear. We utilized the Caenorhabditis elegans and Drosophila homologs of Ataxin‐2 (ATX‐2 and DAtx2, respectively) to determine the role of Ataxin‐2 in ER function and dynamics in embryos and neurons. Loss of ATX‐2 and DAtx2 resulted in collapse of the ER in dividing embryonic cells and germline, and ultrastructure analysis revealed unique spherical stacks of ER in mature oocytes and fragmented and truncated ER tubules in the embryo. ATX‐2 and DAtx2 reside in puncta adjacent to the ER in both C. elegans and Drosophila embryos. Lastly, depletion of DAtx2 in cultured Drosophila neurons recapitulated the shrunken dendritic arbor phenotype of SCA2. ER morphology and dynamics were severely disrupted in these neurons. Taken together, we provide evidence that Ataxin‐2 plays an evolutionary conserved role in ER dynamics and morphology in C. elegans and Drosophila embryos during development and in fly neurons, suggesting a possible SCA2 disease mechanism. 相似文献
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Tongchao Li Junkai Fan Bernardo Blanco-Sánchez Nikolaos Giagtzoglou Guang Lin Shinya Yamamoto Manish Jaiswal Kuchuan Chen Jie Zhang Wei Wei Michael T. Lewis Andrew K. Groves Monte Westerfield Jianhang Jia Hugo J. Bellen 《PLoS genetics》2016,12(5)
Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(23):4748-4765
Casein Kinase I (CKI) is a conserved component of the Wnt signaling pathway, which regulates cell fate determination in metazoans. We show that post-embryonic asymmetric division and fate specification of C. elegans epidermal stem cells are controlled by a non-canonical Wnt/b-catenin signaling pathway, involving the b-catenins WRM-1 and SYS-1, and that C. elegans kin-19/CKIa functions in this pathway. Furthermore, we find that kin-19 is the only member of the Wnt asymmetry pathway that functions with, or in parallel to, the heterochronic temporal patterning pathway to control withdrawal from self-renewal and subsequent terminal differentiation of epidermal stem cells. We show that, except in the case of kin-19, the Wnt asymmetry pathway and the heterochronic pathway function separately and in parallel to control different aspects of epidermal stem cell fate specification. However, given the function of kin-19/CKIa in both pathways, and that CKI, Wnt signaling pathway and heterochronic pathway genes are widely conserved in animals, our findings suggest that CKIa may function as a regulatory hub through which asymmetric division and terminal differentiation are coordinated in adult stem cells of vertebrates. 相似文献
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Marie McGovern Ling Yu Mary Kosinski David Greenstein Cathy Savage-Dunn 《BMC developmental biology》2007,7(1):41