Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5′UTR

Carter, P S; Jarquin-Pardo, Marta; Benedetti, Arrigo De

doi:10.1038/sj.onc.1202890

Cited by 48 publications

(35 citation statements)

References 32 publications

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“…In contrast, high levels of eIF4E activity favor the translation of a specific subset of genes characterized by complex and highly structured 5Ј-UTRs (14). Interestingly, these eIF4E-dependent genes, such as cyclin D1 and c-Myc, are mostly linked with growth-promoting, oncogenic functions (15,16). In agreement with these observations, eIF4E has been defined as a bona fide oncogene (17), and its expression levels are substantially elevated in several types of human cancer including breast and colon, among others (18 -20).…”

supporting

confidence: 57%

“…c-Myc is another major eIF4E target relevant to cell proliferation and transformation (15,41). c-Myc can also be translated through an internal IRES (internal ribosome entry site) within its 5Ј-UTR (42), although this predominantly occurs under certain circumstances such as during mitosis or in apop- totic cells (43,44), and is mostly associated with Myc2 isoform (15). Interestingly, RhoE expression was able to reduce c-Myc protein, but not mRNA, levels and its transcriptional activity upon mitogenic stimulation.…”

Section: Discussionmentioning

confidence: 99%

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RhoE Inhibits 4E-BP1 Phosphorylation and eIF4E Function Impairing Cap-dependent Translation

Villalonga

Mattos

Ridley

2009

Journal of Biological Chemistry

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The Rho GTPase family member RhoE inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have previously reported that RhoE also inhibits cell cycle progression and Ras-induced transformation, specifically preventing cyclin D1 translation. Here we investigate the molecular mechanisms underlying those observations. RhoE inhibits the phosphorylation of the translational repressor 4E-BP1 in response to extracellular stimuli. However, RhoE does not affect the activation of mTOR, the major kinase regulating 4E-BP1 phosphorylation, as indicated by the phosphorylation levels of the mTOR substrate S6K, the dynamics of mTOR/Raptor association, and the observation that RhoE, as opposed to rapamycin, does not impair cellular growth. Interestingly, RhoE prevents the release of the eukaryotic initiation factor eIF4E from 4E-BP1, inhibiting cap-dependent translation. Accordingly, RhoE also inhibits the expression and the transcriptional activity of the eIF4E target c-Myc. Consistent with its crucial role in cell proliferation, we show that eIF4E can rescue both cell cycle progression and Ras-induced transformation in RhoE-expressing cells, indicating that the inhibition of eIF4E function is critical to mediate the anti-proliferative effects of RhoE.Rnd proteins (Rnd1, Rnd2, and RhoE/Rnd3) constitute a separate subfamily within the Rho family of small GTPases that have attracted recent attention because of their atypical features (1). Despite their high level of sequence similarity with RhoA, -B, and -C, Rnd proteins are remarkably different at both biochemical and functional levels. For instance, Rnd proteins do not cycle between an active form and an inactive form. Instead, they are thought to be constitutively GTP bound because of their extremely low GTPase activity and their increased affinity for GTP over GDP. Moreover, both Rnd1 and RhoE/Rnd3 induce opposite effects to those induced by RhoA on the actin cytoskeleton, promoting the disassembly of actin stress fibers and the loss of focal adhesions (2, 3).

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supporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

RhoE Inhibits 4E-BP1 Phosphorylation and eIF4E Function Impairing Cap-dependent Translation

Villalonga

Mattos

Ridley

2009

Journal of Biological Chemistry

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“…In our studies, part of the natural p72 mRNA 5Ј-UTR (in clone 2423 RNA) leads to a complete inhibition of p72 translation in the reticulocyte lysate system (Fig. 2B), and it remains to be analyzed whether the full-length 5Ј-UTR of p72 mRNA exerts a similar inhibitory effect known for other mRNAs with long 5Ј-UTRs as well, like that of c-Myc (48,49). Interestingly, various picornavirus-encoded IRES elements (type I) generally also function poorly in standard cell-free systems (see Ref.…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies ␣-p68-(45-59) (22) were raised against an N-terminal peptide of p68 (amino acids [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] and also recognized p72, which contains two conservative substitutions in this sequence. Affinity purification of polyclonal antibodies was carried out on N-hydroxysuccinimide-activated Sepharose 4 Fast Flow (Amersham Biosciences) to which the respective antigen had been coupled.…”

Section: Methodsmentioning

confidence: 99%

The mRNA of DEAD Box Protein p72 Is Alternatively Translated into an 82-kDa RNA Helicase

Uhlmann‐Schiffler

Rößler

Stahl

2002

Journal of Biological Chemistry

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p68 and p72 are two highly related DEAD box proteins with similar biochemical activities in the nucleus of vertebrate cells; it is unknown whether they have redundant or differential in vivo functions. We report on a third member of this subfamily that is alternatively expressed from p72 mRNA. A detailed analysis of HeLa p72 mRNA was performed. It has an overall length of more than 5 kb and contains a 0.75-kb 5-untranslated region and a 3-untranslated region of 2.5 kb. Its open reading frame extends to nucleotide ؊243 upstream of the first in-frame AUG (A in the AUG triplet is ؉1) which serves as the p72 translation initiator codon. We provide evidence that alternative translation at a non-AUG within the extra coding region of this mRNA yields an 82-kDa protein (p82). Immunological studies substantiate that p82 is a naturally existing p72 variant and that both proteins are expressed at similar concentrations. p82 purified from HeLa cells is an ATP-dependent RNA helicase with biochemical properties almost identical to those of p72.Control of transcription is generally considered the main regulation level of mammalian gene expression, although mRNA maturation and modulation of mRNA stability or translational efficiency also contribute to expression control (1). Generation of protein variants by alternative pre-mRNA splicing or alternative initiation of mRNA translation enlarges the coding capacity and may explain the relatively low number of genes actually found in the human genome. According to recent estimations, on average one gene encodes three proteins (2).Although the 5Ј-untranslated leader sequences (UTRs) 1 of most vertebrate mRNAs are less than 100 nucleotides (nt) long (3), those of tightly controlled genes usually are longer and are GC-rich. Such structure-prone 5Ј-UTRs can modulate translation by the presence of upstream (up) open reading frames (ORFs) in addition to the main ORF, by formation of secondary structures, and/or by RNA-protein interactions (4). Indeed, they appear particularly characteristic of mRNAs encoding growth factors, receptor proteins, transcription factors, signal transduction components, proto-oncogenes, tumor suppressor proteins, and even proteins that mostly are constitutively expressed at a low level ("housekeeping" proteins).DEAD/DEXH box proteins belonging to superfamily II of RNA helicases play a universal role in RNA metabolism of proand eukaryotes. Not surprisingly, they are involved in gene expression control, for instance during germ cell and embryonic development or in cell proliferation and differentiation (5). This in turn requires tight control of at least some DEAD/DEXH box proteins like CsdA of Escherichia coli, which is regulated by an 11-nt "cold box" sequence in its 5Ј-UTR (6), or the Saccharomyces cerevisiae Dbp2, the gene of which contains an unusually large intron that is part of a post-transcriptional autoregulatory feedback loop (7). A similarly complex transcription regulation has been shown for nuclear p68 (8), a mammalian homologue of Dbp2. In addition,...

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“…Deletion mutations in the c-myc 5'UTR, which are present in several Burkitt lymphomas (resulting from translocation of the c-myc gene), result in enhanced translation of the c-Myc mRNA (Saito et al, 1983;Darveau et al, 1985;Parkin et al, 1988;Carter et al, 1999;Willis, 1999). cmyc is implicated in several biological processes such as cell growth, proliferation and apoptosis (reviewed in Gartel and Shchors, 2003;Hermeking, 2003;Levens, 2003;Pelengaris and Khan, 2003).…”

Section: C-mycmentioning

confidence: 99%

eIF4E – from translation to transformation

et al. 2004

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Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5′UTR

Cited by 48 publications

References 32 publications

RhoE Inhibits 4E-BP1 Phosphorylation and eIF4E Function Impairing Cap-dependent Translation

RhoE Inhibits 4E-BP1 Phosphorylation and eIF4E Function Impairing Cap-dependent Translation

The mRNA of DEAD Box Protein p72 Is Alternatively Translated into an 82-kDa RNA Helicase

eIF4E – from translation to transformation

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