The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast
            <i>Saccharomyces cerevisiae</i>

Berset, Catherine; Trachsel, Hans; Altmann, Michael

doi:10.1073/pnas.95.8.4264

Cited by 134 publications

(119 citation statements)

References 47 publications

(43 reference statements)

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“…Furthermore, studies with rapamycin (Figure 7) suggest that the inhibition of protein synthesis per se is not su cient to cause any cleavage of eIF4G in BJAB cells. This is in contrast to the situation in yeast where the factor disappears within 1 ± 2 h of rapamycin treatment (Berset et al, 1998). Another potential mechanism by which cycloheximide might destabilize eIF4G is by promoting the phosphorylation of the 4E-BPs via activation of the mTOR/p70 S6 kinase signalling pathway (Krieg et al, 1988;Brunn et al, 1997;Fadden et al, 1997;Lawrence and Abraham, 1997).…”

Section: Discussionmentioning

confidence: 95%

“…Previous ®ndings have indicated that eIF4G is susceptible to rapid cleavage and disappearance of the full length protein, not only in picornavirusinfected cells Devaney et al, 1988;Kirchweger et al, 1994;Ziegler et al, 1995a) but also in uninfected HeLa cells following antisense RNAmediated down-regulation of eIF4E (De Benedetti et al, 1991), in brain following ischaemia and reperfusion (DeGracia et al, 1996), in erythroleukaemia cells induced to di erentiate with haemin (Benton et al, 1996) and in yeast subjected to nutritional deprivation (Berset et al, 1998). Thus eIF4G seems particularly susceptible to degradation, probably by a number of di erent proteolytic pathways depending on the cell type and stimulus.…”

Section: Discussionmentioning

confidence: 99%

“…In BJAB cells overall protein synthesis is particularly sensitive to rapamycin (Kay et al, 1996), suggesting that the e ects of the drug are not limited to the translation of mRNAs with 5' terminal oligopyrimidine tracts (Je eries et al, 1994; in this system. Thus it was of interest to determine whether inhibition of protein synthesis by this agent would also lead to increased degradation of eIF4G, as has recently been reported for Saccharomyces cerevisiae (Berset et al, 1998). Figure 7a shows that in BJAB cells rapamycin inhibits protein synthesis by about 30% within 30 min, increasing to over 60% within 4 h. Consistent with the mode of action described above, rapamycin caused rapid dephosphorylation of 4E-BP1, together with increased association of 4E-BP1 and decreased association of eIF4G with eIF4E.…”

Section: Is Inhibition Of Protein Synthesis Su Cient To Destabilize Ementioning

confidence: 99%

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Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

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We have investigated the e ect of inducing apoptosis in BJAB and Jurkat cells on the cellular content of several polypeptide chain initiation factors. Serum deprivation results in inhibition of protein synthesis and induction of apoptosis in BJAB cells; at early times, there is selective degradation of polypeptide initiation factor eIF4G but no major losses of other key initiation factors. The disappearance of full length eIF4G is accompanied by the appearance of smaller forms of the protein, including a major product of approximately 76 kDa. Apoptosis induced by cycloheximide results in similar e ects. Both total cytoplasmic eIF4G and eIF4G associated with eIF4E are degraded with a half-life of 2 ± 4 h under these conditions. Treatment of serum-starved or cycloheximide-treated cells with Z-VAD.FMK or Z-DEVD.FMK, which inhibit caspases required for apoptosis, protects eIF4G from degradation and blocks the appearance of the ca. 76 kDa product. Exposure of BJAB cells to rapamycin rapidly inhibits protein synthesis but does not lead to acute degradation of eIF4G. In both BJAB and Jurkat cells induction of apoptosis with anti-Fas antibody or etoposide also results in the selective loss of eIF4G, which is inhibitable by Z-VAD.FMK. These data suggest that eIF4G is selectively targeted for cleavage as cells undergo apoptosis and is a substrate for proteases activated during this process.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Is Inhibition Of Protein Synthesis Su Cient To Destabilize Ementioning

confidence: 99%

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Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

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“…It is possible that decapping is accelerated indirectly by TOR inhibition since translation is dramatically reduced at diauxic shift and after rapamycin treatment (Boucherie, 1985;Fuge et al,1994;Barbet et al, 1996). In particular, several of the translation initiation factors that are believed to protect the 7mG cap from DCP1p (Schwartz and Parker, 2000) are down-regulated at diauxic shift or after rapamycin treatment (DeRisi et al, 1997;Berset et al,1998;Powers and Walter, 1999;Shamji et al, 2000). If changes in translation are responsible for the observed increase in decapping, then it will be important to understand how mRNAs such as the PGK1 transcript, which have been shown to be destabilized when translation initiation is reduced (Muhlrad et al, 1995;Schwartz and Parker, 1999;LaGrandeur and Parker, 1999), are not affected when TOR is inhibited.…”

Section: How Are Decapping and Poly(a) Tail Length Controlled By The mentioning

confidence: 99%

“…Likewise, the treatment of yeast with rapamycin reduces the translation initiation rates to Ͻ50% after only 15 min and to less that 20% after 60 min of exposure (Barbet et al, 1996). The translational down-regulation occurs at several levels, including decreased synthesis of rRNAs (Ju and Warner, 1994;Powers and Walter, 1999), the down-regulation of mRNAs for ribosomal proteins, translation initiation and elongation factors (DeRisi et al, 1997;Powers and Walter, 1999;Shamji et al, 2000), and degradation of the translation initiation factor eIF4Gp (Berset et al,1998). The regulation of mRNA turnover continues to emerge as an important way in which cells control gene expression.…”

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confidence: 99%

The Target of Rapamycin Signaling Pathway Regulates mRNA Turnover in the YeastSaccharomyces cerevisiae

Albig

Decker

2001

MBoC

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The target of rapamycin (TOR) signaling pathway is an important mechanism by which cell growth is regulated by nutrient availability in eukaryotes. We provide evidence that the TOR signaling pathway controls mRNA turnover in Saccharomyces cerevisiae. During nutrient limitation (diauxic shift) or after treatment with rapamycin (a specific inhibitor of TOR), multiple mRNAs were destabilized, whereas the decay of other mRNAs was unaffected. Our findings suggest that the regulation of mRNA decay by the TOR pathway may play a significant role in controlling gene expression in response to nutrient depletion. The inhibition of the TOR pathway accelerated the major mRNA decay mechanism in yeast, the deadenylation-dependent decapping pathway. Of the destabilized mRNAs, two different responses to rapamycin were observed. Some mRNAs were destabilized rapidly, while others were affected only after prolonged exposure. Our data suggest that the mRNAs that respond rapidly are destabilized because they have short poly(A) tails prematurely either as a result of rapid deadenylation or reduced polyadenylation. In contrast, the mRNAs that respond slowly are destabilized by rapid decapping. In summary, the control of mRNA turnover by the TOR pathway is complex in that it specifically regulates the decay of some mRNAs and not others and that it appears to control decay by multiple mechanisms. INTRODUCTIONIt is estimated that most of the microorganisms in the environment exist in conditions in which nutrients are limiting (Lewis and Gattie, 1991). Nutrient availability is very important in controlling cell division, growth, and physiology in microorganisms as well as in multicellular organisms. One critical response in yeast to glucose limitation is the switch from fermentation to respiration, which is termed the diauxic shift. At the diauxic shift, major changes in gene expression are induced (reviewed in Werner-Washburne et al., 1996) including a general repression of translation (Fuge et al., 1994) and extensive changes in the abundance of mRNAs (DeRisi et al., 1997). The target of rapamycin (TOR) signaling pathway senses external nutrient availability and is involved in mediating the changes in gene expression induced at the diauxic shift (reviewed in Cutler et al., 1999;Dennis et al., 1999;Thomas and Hall 1999;Cardenas et al., 1999). Rapamycin artificially induces a starvation-like state in yeast (Barbet et al., 1996) by first forming a complex with the yeast FK506 binding protein, FKBP. This complex then binds to and represses the activity of the TOR1 and TOR2proteins (Heitman et al., 1991). The TOR signaling transduction pathway is conserved among yeast, flies, and mammals. In mammalian cells, the TOR protein homolog mTOR/ FRAP/RAFT1 also coordinates nutrient and mitogenic signals to control cell growth and cell-cycle progression (reviewed in Cutler et al., 1999;Thomas and Hall, 1999). The Drosophila TOR homolog dTOR also senses nutrient availability (Oldham et al., 2000;Zhang et al., 2000). The TOR proteins are protein kinases...

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The Polarised Life of the Endocannabinoid System in CNS Development

Anavi‐Goffer

Mulder

2009

ChemBioChem

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The spatiotemporal expression of cannabinoid receptors and endocannabinoid-metabolising enzymes during brain development guides major developmental processes including neurogenesis, cell differentiation, cell migration, neuronal specification and synaptogenesis.Endocannabinoids (eCBs) play an important role in fine-tuning neurotransmission and have recently been shown to play an important role in brain development. The spatiotemporal expression of cannabinoid receptors and endocannabinoid-metabolising enzymes during development guides major developmental processes including neurogenesis, cell differentiation, cell migration, neuronal specification and synaptogenesis. Furthermore, pharmacological experiments and transgenic animal models have shown the impact of disrupted eCB signalling on normal brain development and revealed the danger of both cannabis abuse and exposure to cannabinoid drugs during embryonic development, childhood and adolescence. In this review, we focus on the dynamic expression of eCB components and the physiological role eCBs play during brain development.

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The TOR (target of rapamycin) signal transduction pathway regulates the stability of translation initiation factor eIF4G in the yeast Saccharomyces cerevisiae

Cited by 134 publications

References 47 publications

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

The Target of Rapamycin Signaling Pathway Regulates mRNA Turnover in the YeastSaccharomyces cerevisiae

The Polarised Life of the Endocannabinoid System in CNS Development

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