TOR controls translation initiation and early G1 progression in yeast.

Abstract

Saccharomyces cerevisiae cells treated with the immunosuppressant rapamycin or depleted for the targets of rapamycin TOR1 and TOR2 arrest growth in the early Gi phase of the cell cycle. Loss of TOR function also causes an early inhibition of translation initiation and induces several other physiological changes characteristic of starved cells entering stationary phase (GO). A Gi cyclin mRNA whose translational control is altered by substitution of the UBI4 5' leader region (UBI4 is normally translated under starvation conditions) suppresses the rapamycin-induced Gl arrest and confers starvation sensitivity. These results suggest that the block in translation initiation is a direct consequence of loss of TOR function and the cause of the Gl arrest. We propose that the TORs, two related phosphatidylinositol kinase homologues, are part of a novel signaling pathway that activates eIF-4E-dependent protein synthesis and, thereby, Gl progression in response to nutrient availability. Such a pathway may constitute a checkpoint that prevents early Gl progression and growth in the absence of nutrients. INTRODUCTIONThe immunosuppressant rapamycin and the related compound FK506 exert their immunosuppressive effects by inhibiting intermediate steps in signal transduction that lead to T cell activation and proliferation (Heitman et al

Simultaneous yet Independent Regulation of Actin Cytoskeletal Organization and Translation Initiation by Glucose inSaccharomyces cerevisiae

“…In contrast to the rapid depolarization after glucose deprivation, the actin cytoskeleton was only gradually depolarized over a period of several hours after a shift from YPD to SCD (Ϫaa) or STMD (ϪNS) ( Figure 2A, e and f; and B). A gradual depolarization was also observed after treatment of cells grown in YPD with rapamycin, which inhibits the TOR protein (Barbet et al, 1996), or after a shift from YPG or YPR to YP (our unpublished data). Thus, the rapid depolarization of the actin cytoskeleton is specific to the abrupt deprivation of glucose.…”

Identification of phosphatase 2A‐like Sit4‐mediated signalling and ubiquitin‐dependent protein sorting as modulators of caffeine sensitivity in S. cerevisiae

“…Thus, TORC1 seems to be a primary target of caffeine in budding yeast; however, the effects of rapamycin and caffeine are clearly not identical. For example, whereas rapamcyin induces a G 1 cell cycle arrest (Barbet et al, 1996), the growth inhibition caused by caffeine is asynchronous (Kuranda et al, 2006). Whereas TORC2 function is insensitive to rapamycin (Wullschleger et al, 2006), several genetic results suggest that it is sensitive to caffeine (deHart et al, 2003;Ho et al, 2005;Reinke et al, 2006).…”

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

“…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 TOR2…”

“…Translation also undergoes dramatic changes at diauxic shift with translation rates decreasing to 2-25% of log-phase values (Boucherie, 1985;Fuge et al,1994). 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).…”