Multiple eIF4GI-Specific Protease Activities Present in Uninfected and Poliovirus-Infected Cells

Zamora, Miguel; Marissen, Wilfred Ε.; Lloyd, Richard E.

doi:10.1128/jvi.76.1.165-177.2002

Cited by 46 publications

(44 citation statements)

References 52 publications

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“…It is known that in cells infected with picornaviruses, the integrity of eIF4G declines after infection due to cleavage of eIF4G by viral and/or cellular proteases (18,68). This cleavage destroys the bridging function of eIF4G in protein synthesis and leads to the inhibition of cap-dependent initiation (18).…”

Section: Discussionmentioning

confidence: 99%

Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F

Sans

DiMagno

DʼAlecy

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F. Am J Physiol Gastrointest Liver Physiol 285: G517-G528, 2003. First published May 28, 2003 10.1152/ajpgi.00540.2002.-Acute pancreatitis (AP) has been shown in some studies to inhibit total protein synthesis in the pancreas, whereas in other studies, protein synthesis was not affected. Previous in vitro work has shown that high concentrations of cholecystokinin both inhibit protein synthesis and inhibit the activity of the guanine nucleotide exchange factor eukaryotic initiation factor (eIF)2B by increasing the phosphorylation of eIF2␣. We therefore evaluated in C57BL /6 mice the effects of caerulein-induced AP on pancreatic protein synthesis, eIF2B activity and other protein translation regulatory mechanisms. Repetitive hourly injections of caerulein were administered at 50 g/kg ip. Pancreatic protein synthesis was reduced 10 min after the initial caerulein administration and was further inhibited after three and five hourly injections. Caerulein inhibited the two major regulatory points of translation initiation: the activity of the guanine nucleotide exchange factor eIF2B (with an increase of eIF2␣ phosphorylation) and the formation of the eIF4F complex due, in part, to degradation of eIF4G. This inhibition was not accounted for by changes in the upstream stimulatory pathway, because caerulein activated Akt as well as phosphorylating the downstream effectors of mTOR, 4E-BP1, and ribosomal protein S6. Caerulein also decreased the phosphorylation of the eukaryotic elongation factor 2, implying that this translation factor was not inhibited in AP. Thus the inhibition of pancreatic protein synthesis in this model of AP most likely results from the inhibition of translation initiation as a result of increased eIF2␣ phosphorylation, reduction of eIF2B activity, and the inhibition of eIF4F complex formation. protein translation; mice IT HAS BEEN WELL ESTABLISHED that experimental acute pancreatitis (AP) inhibits pancreatic exocrine secretion (32,36,55,60). It has also been reported that pancreatic protein synthesis is unaffected by AP, leading to accumulation of digestive enzymes (5,30,55,60). However, other studies have shown inhibition of pancreatic protein synthesis in both in vivo experimental AP studies (17,26,32,36,46) and in vitro models of AP using CCK hyperstimulation of isolated acini (31,48,56). This study seeks to clarify how protein synthesis is affected in an in vivo caerulein hyperstimulation model of AP in mice, using the "flooding dose" technique to measure protein synthesis and by analyzing the state of key regulatory mechanisms in protein translation.Protein synthesis or translation of mRNA into protein has several known major regulatory steps involving initiation and elongation phases. The first major step in translation initiation is the binding of the initiator tRNA iMet to the 40 S ribosomal subunit, which is regulated by the eukaryotic initiation factor (eIF)2 (27, 51). In order for eIF2 to p...

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Section: Discussionmentioning

confidence: 99%

Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F

Sans

DiMagno

DʼAlecy

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…pro (Bovee et al 1998;Zamora et al 2002). To distinguish between these possibilities we generated stable HeLa cell lines with tet-inducible expression of myctagged eIF4GI-b or the Ct fragment (Fig.…”

Section: Stable Cell Lines With Inducible Expression Of Eif4gi Proteinsmentioning

confidence: 99%

Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

Kaiser¹,

Dobrikova²,

Bradrick³

et al. 2008

RNA

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Protein synthesis is tightly controlled by assembly of an intricate ribonucleoprotein complex at the m 7 GTP-cap on eukaryotic mRNAs. Ensuing linear scanning of the 59 untranslated region (UTR) is believed to transfer the preinitiation complex to the initiation codon. Eukaryotic mRNAs are characterized by significant 59 UTR heterogeneity, raising the possibility of differential control of translation initiation rate at individual mRNAs. Curiously, many mRNAs with unconventional, highly structured 59 UTRs encode proteins with central biological roles in growth control, metabolism, or stress response. The 59 UTRs of such mRNAs may influence protein synthesis rate in multiple ways, but most significantly they have been implicated in mediating alternative means of translation initiation. Cap-independent initiation bypasses strict control over the formation of initiation intermediates at the m 7 GTP cap. However, the molecular mechanisms that favor alternative means of ribosome recruitment are not understood. Here we provide evidence that eukaryotic initiation factor (eIF) 4G controls cap-independent translation initiation at the c-myc and vascular endothelial growth factor (VEGF) 59 UTRs in vivo. Cap-independent translation was investigated in tetracycline-inducible cell lines expressing either full-length eIF4G or a C-terminal fragment (Ct) lacking interaction with eIF4E and poly(A) binding protein. Expression of Ct, but not intact eIF4G, potently stimulated cap-independent initiation at the c-myc/VEGF 59 UTRs. In vitro RNA-binding assays suggest that stimulation of cap-independent translation initiation by Ct is due to direct association with the c-myc/VEGF 59 UTR, enabling 43S preinitiation complex recruitment. Our work demonstrates that variant translation initiation factors enable unconventional translation initiation at mRNA subsets with distinct structural features.

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“…This can be exemplified by the repression of cap-dependent translation that occurs in poliovirus-infected cells. Infection results in proteolytic cleavage of hostcell translation factors (e.g., eIF4G) that abrogate eIF4F-mediated recruitment of the 40S subunit to the majority of capped, cellular mRNAs (Bovee et al 1998;Gale et al 2000;Kuyumcu-Martinez et al 2002;Zamora et al 2002). Despite this, translation of viral RNA persists (Johannes et al 1999) due to the cap-independent recruitment of the 40S ribosomal subunit to an IRES located within the 5Ј-UTR of the viral RNA (Schmid and Wimmer 1994).…”

Section: Introductionmentioning

confidence: 99%

Translation of cellular inhibitor of apoptosis protein 1 (c-IAP1) mRNA is IRES mediated and regulated during cell stress

Eden

Byrd²,

Sherrill³

et al. 2004

RNA

Self Cite

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Cellular inhibitor of apoptosis protein 1 (c-IAP1) can regulate apoptosis through its interaction with downstream TNF receptor effectors (TRAF1 and TRAF2), by binding to and inhibiting certain caspases, and by controlling the levels of specific proapoptotic stimuli (e.g., Smac/DIABLO) within the cell. Studies involving the expression of c-IAP1 mRNA and protein in cells and tissues have provided evidence suggesting c-IAP1 expression may be posttranscriptionally controlled. Because the 5-UTR of c-IAP1 mRNA is unusually long, contains multiple upstream AUG codons, and has the potential to form thermodynamically stable secondary structures, we investigated the possibility it contained an internal ribosome entry site (IRES) that may regulate its expression. In the present study, the c-IAP1 5-UTR exhibited IRES activity when dicistronic RNA constructs were translated in rabbit reticulocyte lysate (RRL) and in transiently transfected cells. IRES-mediated translation was similar to that exhibited by the hepatitis C virus IRES but varied significantly in RRL and in HeLa, HepG2, and 293T cells, indicating the c-IAP1 IRES was system and cell type specific. IRES-mediated translation was maintained in mono-and dicistronic constructs in which the UTR was inserted downstream from a stable hairpin that prevented cap-dependent ribosome scanning. In cells, the presence or absence of a methylated cap did not significantly affect the translation of polyadenylated, monocistronic RNAs containing the c-IAP1 5-UTR. IRES-mediated translation was stimulated in transfected cells treated with low doses of pro-apoptotic stimuli (i.e., etoposide and sodium arsenite) that inhibited endogenous cellular translation.

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Multiple eIF4GI-Specific Protease Activities Present in Uninfected and Poliovirus-Infected Cells

Cited by 46 publications

References 52 publications

Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F

Caerulein-induced acute pancreatitis inhibits protein synthesis through effects on eIF2B and eIF4F

Activation of cap-independent translation by variant eukaryotic initiation factor 4G in vivo

Translation of cellular inhibitor of apoptosis protein 1 (c-IAP1) mRNA is IRES mediated and regulated during cell stress

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