A Signaling Pathway to Translational Control

Abstract

facility for mRNAs. Rapamycin treatment inhibits each of these growth factor-stimulated effects (Jefferies et Howard Hughes Medical Institute al., 1994; Terada et al., 1994; Nielsen et al., 1995). Since Department of Chemistry and Chemical Biology the change in association of these mRNAs with polyribo-and Program in Immunology somes indicates that these transcripts are regulated at Harvard University the initiation phase, the signaling pathway inhibited by 12 Oxford St.rapamycin appears to regulate early steps in the transla-Cambridge, Massachusetts 02138 tion process. Regulation by the 5 Untranslated RegionTranslation initiation is generally the rate limiting step Over twenty years ago, an obligatory role for protein in the overall process and is influenced by elements translation in G1 cell cycle progression was brought to within the 5Ј untranslated region (UTR) of the mRNA. light (reviewed by Norbury and Nurse, 1992). TransitThe rapamycin-sensitive translation of an IGF-II mRNA through the cell cycle is thought to require a general appears to be regulated by such a mechanism. Tranincrease in the rate of translation following growth facscripts of the hormone IGF-II are alternatively spliced tor-stimulation; in fact, even a partial inhibition of protein to produce multiple mRNAs that differ only in their 5Ј synthesis causes fibroblasts to accumulate in the G1UTRs. The translation of two such splice variants (4.8 phase (Norbury and Nurse, 1992). It is now well known and 6.0 kb) are discordant in their sensitivity to rapathat growth factor stimulation causes a 2-3 fold mean mycin treatment. While the 4.8 kb message is translated increase in overall protein synthesis, implicating transequally in rapamycin treated and untreated cells, transmembrane signaling events in translational control (relation of the 6.0 kb transcript is both rapamycin-sensitive viewed by Sonenberg, 1996). This average increase apand dependent on the presence of growth factors (Nielpears modest; however, while translation of some sen et al., 1995). Thus, the 1.2 kb leader sequence in transcripts remains unaffected by mitogen stimulation, the 5Ј UTR of the 6.0 kb variant confers translational others increase greatly (discussed below). Although our regulation to this gene. understanding of the events that regulate gene expres-What structural elements in 5Ј UTRs may be involved sion through transcription has made steady progress, in their translational regulation? One element implicated the signal transduction pathways involved in translain the regulated translation of transcripts encoding ribotional control have remained relatively uncharacterized.somal proteins and the eukaryotic elongation factors 1A Catalyzed through use of cell-permeable inhibitors of and 2 (eEF1A and eEF2) is the polypyrimidine tract. This cell cycle progression, one signaling pathway that leads 5Ј terminal oligopyrimidine tract (5Ј TOP) typically conto translational control has recently become better unsists of a stretch of 4-14 pyrimidines following the N 7derstood. Thi...

Therapeutic targets: MTOR and related pathways

“…Unphosphorylated 4E-BP1 binds to RNA cap-binding protein eIF-4E, inhibiting its coupling to mRNA and the translational initiation complex required for initiating translation of cap-dependent mRNAs, a subset of mRNAs with regulatory elements located in the 5'-untranslated regions (UTRs). 16 Activated mTOR, leads to phosphorylation of 4E-BP1, release of eIF-4E to bind to cap mRNA transcripts and other initiation complex proteins, and the initiation of cap-dependent translation. 4 This interaction results in an increase in translation rates cap-dependent mRNAs, including several proteins controlling cell proliferation.…”

Efficacy of exercise, losartan, enalapril, atenolol and rilmenidine in subjects with blood pressure hyperreactivity at treadmill stress test and left ventricular hypertrophy

“…Angiotensin II increases the release of norepinephrine in presynaptic junctions, increases the pressure response to norepinephrine and increases the sympathetic tonus. 37 One of the hypotheses for the result found was that in such subjects the trigger for the development of LVH would be a RAS hyperactivity, or its predominance over the SNS. This initial hypothesis we present seems to be in accordance with what Polonia et al 8 assumed when, following catecolamine dosage in subjects with such characteristics, they suggested the hypothesis of sympathetic hyperactivity for such phenomenon.…”

ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK

“…This protein consists of a 460 kDa catalytic subunit whose kinase activity is enhanced by ends of DNA molecules in the presence of the co-factors Ku70 and 86 (Jackson and Jeggo, 1995). In addition, the PIK family includes the TOR proteins, which are targets of the FKBP-rapamycin complex (Brown and Schreiber, 1996;Hall, 1996), and the ataxia telangiectasia gene product, ATM (Savitsky et al, 1995). A subset of the PIK family contains an additional region of homology termed the rad3 homologous region, and this subfamily includes the S. cerevisiae MEC1 and TEL1 (Greenwell et al, 1995;Morrow et al, 1995) and the Drosophila mei-41 gene product (Hari et al, 1995).…”