Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1

Cobbold, Laura C.; Wilson, Lindsay A.; Sawicka, Kirsty; King, H. W.; Kondrashov, Alexander; Spriggs, Keith A.; Bushell, Martin; Willis, Anne E.

doi:10.1038/onc.2010.31

Cited by 94 publications

(83 citation statements)

References 32 publications

(41 reference statements)

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“…In another parallel with hnRNP A1, PTB has been found to bind to the c-Myc IRES sequence, where it up-regulates c-Myc translation synergistically with another RBP, YB-1 (Cobbold et al 2010). Cobbold et al (2010) found a striking correlation between c-Myc and PTB protein levels, both of which were elevated in multiple myeloma cell lines compared with B-cell lines. A similar correlation between c-Myc and PTB (as well as hnRNP A1/A2) levels was observed in gliomas .…”

Section: Hnrnp and Sr Proteins In Proliferation And Cancermentioning

confidence: 89%

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

712

667

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Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.

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Section: Hnrnp and Sr Proteins In Proliferation And Cancermentioning

confidence: 89%

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

712

667

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“…5C). Among the egr2-59UTR binding proteins, we found PTB, hnRNP-A1, and human antigen R (HuR), all of which were previously shown to act as ITAFs associated with enhanced translation of target mRNAs (Vagner et al 2001;Bonnal et al 2005;Cobbold et al 2010). To ensure an RNA-specific binding of these proteins to the egr2-59UTR, the interaction was further verified via RNA-affinity purification, followed by Western analysis, including a control RNA of similar length (300 nt) encoding a fraction of FIGURE 3.…”

Section: Various Itafs Bind To the 59 Utr Of Egr2mentioning

confidence: 99%

IRES-dependent translation of egr2 is induced under inflammatory conditions

Rübsamen

Blees

Schulz

et al. 2012

RNA

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Adjusting translation is crucial for cells to rapidly adapt to changing conditions. While pro-proliferative signaling via the PI3K-mTOR-pathway is known to induce cap-dependent translation, stress conditions, such as nutrient deprivation or hypoxia often activate alternative modes of translation, e.g., via internal ribosome entry sites (IRESs). As the effects of inflammatory conditions on translation are only poorly characterized, we aimed at identifying translationally deregulated targets in inflammatory settings. For this purpose, we cocultured breast tumor cells with conditioned medium of activated monocyte-derived macrophages (CM). Polysome profiling and microarray analysis identified early growth response-2 (egr2) to be regulated at the level of translation. Using bicistronic reporter assays, we found that egr2 contains an IRES within its 59 UTR, which facilitated enhanced translation upon CM treatment. We further provide evidence that the activity of egr2-IRES was induced by IL-1b and p38-MAPK signaling. In addition, we identified several potential IRES trans-acting factors (ITAFs) such as polypyrimidine tract binding protein (PTB) and hnRNP-A1 that directly bind to the egr2-59UTR. In summary, our data provide evidence that egr2 expression is translationally regulated via an IRES element, which is responsive to an inflammatory environment.

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“…In addition, IRES mutations or deregulated IRES-trans-acting factors (ITAF) can further increase the translation of oncogenic proteins. In multiple myeloma, mutations in c-myc-IRES were shown to enhance its translation initiation (19), and a more recent study in the same cancer type (20) showed an increase in IRES-dependent c-myc translation via ITAFs such as Y-box binding protein 1 (YB-1) and polypyrimidine tract-binding protein 1 (PTB-1), which were previously reported to be involved in carcinogenesis and chemotherapy resistance (21)(22)(23)(24). These findings both show the importance of IRES-driven carcinogenesis and have therapeutic implications.…”

Section: Ires-mediated Translationmentioning

confidence: 99%

Translation Regulation as a Therapeutic Target in Cancer

Grzmil

Hemmings

2012

Cancer Research

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Protein synthesis is a vital cellular process that regulates growth and metabolism. It is controlled via signaling networks in response to environmental changes, including the presence of nutrients, mitogens, or starvation. The phosphorylation state of proteins involved in translation initiation is a limiting factor that regulates the formation or activity of translational complexes. In cancer cells, hyperactivated signaling pathways influence translation, allowing uncontrolled growth and survival. In addition, several components of translation initiation have been found to be mutated, posttranslationally modified, or differentially expressed, and some act as oncogenes in cancer cells. Translational alterations can increase the overall rate of protein synthesis as well as activate regulatory mechanisms leading to the translation of specific messenger RNAs for proteins that promote cancer progression and survival. Many recent studies investigating such mechanisms have produced ideas for therapeutic intervention. This review describes altered mechanisms of protein synthesis in human cancers and discusses therapeutic approaches based on the targeting of translation. Cancer Res; 72(16); 3891-900. Ó2012 AACR.

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Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1

Cited by 94 publications

References 32 publications

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

IRES-dependent translation of egr2 is induced under inflammatory conditions

Translation Regulation as a Therapeutic Target in Cancer

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