PHAS-I as a Link Between Mitogen-Activated Protein Kinase and Translation Initiation

Lin, Teng Nan; Kong, Xianming; Haystead, Timothy; Pause, Arnim; Belsham, Graham J.; Sonenberg, Nahum; Lawrence, John C.

doi:10.1126/science.7939721

Cited by 641 publications

(588 citation statements)

References 19 publications

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“…In agreement with numerous previous studies (see for example, Lin et al, 1994;Graves et al, 1995;Gingras et al, 1996;Mendez et al, 1996), mouse and human 4E-BP1 were detected as multiple bands on gels in the vicinity of 20 kDa. These correspond to differentially phosphorylated forms, with hyperphosphorylated (g) 4E-BP1 migrating more slowly than the less phosphorylated (b and a) forms.…”

Section: Identification Of High-molecular-weight Forms Of 4e-bp1supporting

confidence: 93%

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

2007

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The availability of the eukaryotic polypeptide chain initiation factor 4E (eIF4E) for protein synthesis is regulated by the 4E-binding proteins (4E-BPs), which act as inhibitors of cap-dependent mRNA translation. The ability of the 4E-BPs to sequester eIF4E is regulated by reversible phosphorylation at multiple sites. We show here that, in addition, 4E-BP1 is a substrate for polyubiquitination and that some forms of 4E-BP1 are simultaneously polyubiquitinated and phosphorylated. In Jurkat cells inhibition of proteasomal activity by MG132 enhances the level of hypophosphorylated, unmodified 4E-BP1 but only modestly increases the accumulation of high-molecularweight, phosphorylated forms of 4E-BP1. In contrast, inhibition of protein phosphatase activity with calyculin A reduces the level of unmodified 4E-BP1 but strongly enhances the amount of phosphorylated, high-molecularweight 4E-BP1. Turnover measurements in the presence of cycloheximide show that, whereas 4E-BP1 is normally a very stable protein, calyculin A decreases the apparent half-life of the normal-sized protein. Affinity chromatography on m 7 GTP-Sepharose indicates that the larger forms of 4E-BP1 bind very poorly to eIF4E. We suggest that the phosphorylation of 4E-BP1 may play a dual role in the regulation of protein synthesis, both reducing the affinity of 4E-BP1 for eIF4E and promoting the conversion of 4E-BP1 to alternative, polyubiquitinated forms.

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Section: Identification Of High-molecular-weight Forms Of 4e-bp1supporting

confidence: 93%

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

2007

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“…These results suggest that Ang II activates p70 s6K through the pathway different from that of MAP kinases/p90 rsk. Recently it has been reported that MAP kinases phosphorylate PHAS-I, which is a heat-stable protein found in many tissues including the heart and the phosphorylated PHAS-I dissociates from translation initiation factor 4E, resulting in the initiation of translation [33]. Therefore, it is possible that the activations of both p70 s6K and MAP kinases are necessary for Ang II-induced cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Activation of p70 S6 protein kinase is necessary for angiotensin II‐induced hypertrophy in neonatal rat cardiac myocytes

et al. 1996

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Although many lines of evidence have suggested that angiotensin II (Ang II) plays an important role in development of cardiac hypertrophy, the mechanism by which Ang II increases protein synthesis in cardiac myocytes remains unclear. It has been reported that the phosphorylation of $6 protein in 40 S ribosome is correlated to the efficiency of protein synthesis. In the present study, we have examined whether Ang II activates p70 $6 kinase (p70S6g), which has been reported to phosphorylate $6 protein.

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“…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%

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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PHAS-I as a Link Between Mitogen-Activated Protein Kinase and Translation Initiation

Cited by 641 publications

References 19 publications

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

Effects of protein phosphorylation on ubiquitination and stability of the translational inhibitor protein 4E-BP1

Activation of p70 S6 protein kinase is necessary for angiotensin II‐induced hypertrophy in neonatal rat cardiac myocytes

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

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