A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: A novel mechanism of oncogene de-regulation

Chappell, Stephen A.; LeQuesne, John; Paulin, Fiona E.M.; deSchoolmeester, Matthew L.; Stoneley, Mark; Soutar, Richard; Ralston, Stuart H.; Helfrich, Miep; Willis, Anne E.

doi:10.1038/sj.onc.1203791

Cited by 127 publications

(91 citation statements)

References 29 publications

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“…Equal amounts of extract were used to assay cap-dependent translation of Renilla luciferase (R-Luc) or IRES-dependent translation of firefly luciferase (F-Luc), using a dual-luciferase reporter assay system. Cap-dependent translation was calculated by normalizing the R-Luc activity to the F-Luc activity, as described previously (26,27).…”

Section: Methodsmentioning

confidence: 99%

“…4, A and B). mTORC1 regulates capdependent translation through phosphorylation of 4EBP1, which releases 4EBP1 from eIF-4E and promotes translation initiation (32), so we further examined the effects of Crbn deficiency on cap-dependent translation using a relative luciferase assay (26,27). As shown in Fig.…”

Section: Crbn Deficiency Reduces the Activity Of Mtor In The Brain-mentioning

confidence: 99%

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Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Lee

Yang

Choi

et al. 2014

Journal of Biological Chemistry

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Background: Deficiency or nonsense mutation of CRBN causes memory deficits. Results: Truncated CRBN has insufficient affinity for AMPK␣ and cannot modulate the AMPK-mTOR pathway. Conclusion: CRBN modulates protein synthesis through the AMPK-mTOR pathway, and may be critical for certain forms of memory encoding. Significance: Our findings suggest the first plausible mechanism for the phenotype resulting from the CRBN mutation.

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Section: Methodsmentioning

confidence: 99%

Section: Crbn Deficiency Reduces the Activity Of Mtor In The Brain-mentioning

confidence: 99%

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Lee

Yang

Choi

et al. 2014

Journal of Biological Chemistry

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“…Subsequently, the same sequence substitution was identified in 42% of bone marrow samples collected from MM patients. This mutation enhances the activity of the c-myc IRES and its effect is particularly pronounced in MM cell lines (Chappell et al, 2000b). It is known that the C to U transition can stabilize the formation of RNA-protein complexes containing the cmyc IRES .…”

Section: Internal Initiation and Tumorigenesismentioning

confidence: 99%

Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression

2004

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Initiation of translation in eukaryotic cells can occur by two distinct mechanisms, cap-dependent scanning and internal ribosome entry. The latter mechanism requires the formation of a complex RNA structural element termed an internal ribosome entry segment (IRES). IRESs are located in the 5 0 untranslated region of the message, and in the presence of trans-acting factors allow the ribosome to be recruited to a site that is a considerable distance from the cap structure. Many cellular mRNAs have now been shown to contain IRESs and it is likely that up to 10% of all mRNAs have the capability to initiate translation by this mechanism. The majority of IRESs that have been identified thus far are found in mRNAs whose protein products are associated with the control of cell growth and cell death, including many growth factors, proto-oncogenes and proteins required for apoptosis. In this review, we discuss the cellular situations when IRESs are required, the trans-acting factors that are necessary for IRES function and deregulation of IRES-mediated translation in tumorigenesis.

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“…HnRNPK was found to bind to the 3 0 end of the RNA (Figure 5b) and one putative site present in this section of RNA is from 254-259 UCCCGA. Interestingly, we have shown previously that in 42% of patients with MM this site is mutated (Chappell et al, 2000) to UCUCGA. Further studies were therefore carried out to investigate the binding of PCBP1 and PCBP2 to the c-myc IRES and to test the whether the mutated version of the IRES had a different affinity for hnRNPK.…”

Section: Uv Crosslinking Analysis Shows That the C-myc Ires Interactsmentioning

confidence: 99%

“…This increased c-Myc protein expression in MMderived cell lines correlates with a C-T mutation in the region of c-myc DNA that contains the IRES (Paulin et al, 1996) and RNA derived from the mutant IRES displays enhanced binding of protein factors . The C-T mutation is also present in the cells derived from the bone marrow of MM patients (42%) and this mutation alters translation initiation via the IRES (Chappell et al, 2000) demonstrating that a single mutation in the c-myc IRES is sufficient to cause enhanced initiation of translation via internal ribosome entry.…”

Section: Introductionmentioning

confidence: 99%

Members of the poly (rC) binding protein family stimulate the activity of the c-myc internal ribosome entry segment in vitro and in vivo

et al. 2003

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The 5 0 untranslated region of the proto-oncogene c-myc contains an internal ribosome entry segment and c-Myc translation can be initiated by cap-independent as well as cap-dependent mechanisms. In contrast to the process of cap-dependent initiation, the trans-acting factor requirements for cellular internal ribosome entry are poorly understood. Here, we show that members of the poly (rC) binding protein family, poly (rC) binding protein 1 (PCBP1), poly (rC) binding protein 2 (PCBP2) and hnRNPK were able to activate the IRES in vitro up to threefold when added in combination with upstream of N-ras and unr-interacting protein. The interactions of PCBP1, PCBP2 and hnRNPK with c-myc-IRES-RNA were shown to be specific by ultraviolet crosslinking analysis and electrophoretic mobility shift assays, while immunoprecipitation of the three proteins using specific antibodies followed by reverse transcriptase-polymerase chain reaction showed that they were able to bind c-myc mRNA. c-myc-IRES-mediated translation from the reporter vector was stimulated by cotransfection of plasmids encoding PCBP1, PCBP2 and hnRNPK. Interestingly, the mutated version of the c-myc IRES that is prevalent in patients with multiple myeloma bound hnRNPK more efficiently in vitro and was stimulated by hnRNPK to a greater extent in vivo.

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A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: A novel mechanism of oncogene de-regulation

Cited by 127 publications

References 29 publications

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

Cellular internal ribosome entry segments: structures, trans-acting factors and regulation of gene expression

Members of the poly (rC) binding protein family stimulate the activity of the c-myc internal ribosome entry segment in vitro and in vivo

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