Identification of Phosphorylation Sites in the Translational Regulator, PHAS-I, That Are Controlled by Insulin and Rapamycin in Rat Adipocytes

Fadden, Patrick; Haystead, Timothy A.J.; Lawrence, John C.

doi:10.1074/jbc.272.15.10240

Cited by 175 publications

(195 citation statements)

References 46 publications

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“…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). This would have the e ect of dissociating eIF4E from the 4E-BPs and favouring its association with eIF4G (Graves et al, 1995;Von Manteu el et al, 1996;Brunn et al, 1997), thus potentially altering the conformation of the latter (Ohlmann et al, 1997).…”

Section: Discussionmentioning

confidence: 96%

“…The 4E-binding proteins are reversibly phosphorylated in response to conditions which stimulate translation (Lin et al, 1994Lin and Lawrence, 1996;Fadden et al, 1997;Lawrence and Abraham, 1997) and this process favours Figure 4 Changes in levels of initiation factors in cycloheximide-treated BJAB cells. Exponentially growing cells were treated with cycloheximide (100 mg/ml) for the times indicated and cytoplasmic extracts prepared as described in Materials and methods.…”

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

confidence: 99%

“…The extent of complex formation between the best studied of these proteins, 4E-BP1 (also known as PHAS-I) (Lawrence and , and eIF4E is regulated by the phosphorylation of 4E-BP1 (Graves et al, 1995;Von Manteu el et al, 1996;Brunn et al, 1997). This phosphorylation is activated by a pathway which can be inhibited by the macrolide immunosuppressant, rapamycin Von Manteu el et al, 1996;Beretta et al, 1996a;Fadden et al, 1997;Brunn et al, 1997). As a result rapamycin inhibits cap-dependent initiation (Beretta et al, 1996a,b), as well as antagonizing increases in protein synthesis brought about by mitogenic stimuli .…”

Section: Introductionmentioning

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: 96%

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

confidence: 99%

Section: Introductionmentioning

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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“…A critical event is the phosphorylation of 4E-binding protein [4E-BP1 ; PHAS (pH-and acid-stable)-I] and its dissociation from eukaryotic initiation factor 4E, leading to mRNA translation. This phosphorylation occurs at multiple residues and appears to involve PI-3K and p70 S'K , since it is wortmannin-and rapamycinsensitive [88][89][90]. Since PKB activation is also wortmanninsensitive and can contribute to p70 S'K activation [24], it may play a role in the regulation of insulin-mediated protein synthesis.…”

Section: Protein Synthesismentioning

confidence: 99%

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Coffer

Jin

Woodgett

1998

Biochemical Journal

988

818

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While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membranerestricted second messenger, polyphosphatidylinositides containing a 3h-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3h-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)\AKT and PtdIns(3,4,5)P $ -dependent kinases 1 and 2, the first two of which interact with 3h-phosphorylated ORIGINS OF AKTThe AKR strain of mice exhibit a high incidence of leukaemias and lymphomas from spontaneous thymoma [1]. A retrovirus termed AKT8 was isolated from one of these lines derived from a spontaneous thymoma. This virus was demonstrated to uniquely transform only mink lung cells (CCL64) in culture, while virus inoculated into newborn mice was shown to be tumorigenic [2]. The non-viral DNA component transduced from the mouse genome was subsequently identified, and two human homologues, AKT1 and AKT2, cloned [3]. The location of the human AKT locus was mapped to chromosome 14q32, proximal to the immunoglobulin-heavy-chain locus [4], a region frequently affected by translocations and inversions in human Tcell leukaemia\lymphoma, mixed-lineage childhood leukaemia and clonal T-cell proliferations in ataxia telangiectasia, supporting a role for this oncogene in formation of a variety of tumours [5]. Analysis of a panel of human tumours revealed a 20-fold amplification of AKT1 in a primary gastric adenocarcinoma. AKT2, on the other hand, was mapped to chromosome region 19q13.1-q13.2 and shown to be amplified and overexpressed in several ovarian carcinoma and pancreatic cancer cell lines [6,7]. A recent large-scale study of AKT2 alterations in ovarian and breast tumours revealed amplification in 12.1 % ovarian and 2.8 % breast carcinomas [8]. Furthermore, amplification of AKT2 was especially frequent in undifferentiated tumours, suggesting that AKT2 alterations may be associated with tumour aggressiveness.Abbreviations used : PI-3K, phosphatidylinositol 3-kinase ; PKB, protein kinase B ; PKA, protein kinase A ; PKC, protein kinase C ; RAC-PK, related to A-and C-kinase ; PH, pleckstrin homology ; PtdIns, phosphoinositide ; PDGF, platelet-derived growth factor ; EGF, epidermal growth factor ; bFGF, basic fibroblast growth factor ; IL, interleukin ; ERK, extracellular-signal-regulated kinase ; Btk, Bruton tyrosine kinase ; PDK, PtdIns(3,4,5)P 3 -dependent kinase ; MAPKAP, mitogen-activated protein kinase-activated protein ; SH2, Src homology 2 ; gag, group-specific antigen ; GLUT, glucose transporter ; GSK, glycogen synthase kinase ; PFK2, 6-phosphofructose-2-kinase ; IGF, insulin-like growth factor ; 4E-BP1, 4E-binding protein ; PHAS, pH-and acid-stable ; BCR-ABL, breakpoint...

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“…The major physiological S6 protein kinase of mammalian cells, p70 S6k , is thought to lie on the same overall signalling pathway as 4E-BP1, although the pathway appears to divide above 4E-BP1 and p70 S6k (Fadden et al, 1997;von Manteuffel et al, 1997), and p70 S6k does not phosphorylate 4E-BP1 directly (Diggle et al, 1996). Burnett et al (1998) have presented data indicating that the rapamycin target protein RAFT may act as a 4E-BP1 kinase both in vitro and in vivo.…”

Section: Activity Of P70 S6 Kinase Is Enhanced But Rapamycin-sensitivmentioning

confidence: 99%

Rapamycin-resistant phosphorylation of the initiation factor-4E-binding protein (4E-BP1) in v-SRC-transformed hamster fibroblasts

et al. 1999

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Identification of Phosphorylation Sites in the Translational Regulator, PHAS-I, That Are Controlled by Insulin and Rapamycin in Rat Adipocytes

Cited by 175 publications

References 46 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

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Rapamycin-resistant phosphorylation of the initiation factor-4E-binding protein (4E-BP1) in v-SRC-transformed hamster fibroblasts

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