Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The third exon of the c-myc gene contains a CpG site which has been implicated as a regulatory region. When this site is methylated it has protein binding properties and binds a different set of proteins in normal and neoplastic cells. Recent work using myeloma cell lines indicates a correlation between hypomethylation at this site and enhanced expression of the myc protein. We investigated the methylation of this site in 10 cases of myeloma but found that there was no change from the high degree of methylation found in normal cells. Therefore, methylation status at this site is unlikely to serve as a prognosticator in myelomatosis. However, methylation changes at this site were observed in DNA from two cases of CMML, in which hypomethylation was observed and in three AML cases, which were completely methylated at this site.
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PMID:Methylation status within exon 3 of the c-myc gene as a prognostic marker in myeloma and leukaemia. 768 Jul 37

A 340 nucleotide section of the c- myc 5' untranslated region (UTR) contains an internal ribosome entry segment. We have described previously a mutation in this region of RNA in cell lines derived from patients with multiple myeloma (MM) which exhibit increased expression of c- myc protein by an aberrant translational mechanism. In this study we show by electrophoretic mobility shift assays (EMSA), north-western blotting and UV cross-linking that radiolabelled c- myc 5' UTR RNA transcripts which harbour the mutation cause enhanced binding of cellular proteins. In addition, we also demonstrate that an MM derived cell line possesses an altered repertoire of RNA binding proteins. Our data suggest that the deregulated expression of c -myc in MM could result both from the effect of the mutation and the additional proteins which are present in these cell types.
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PMID:A single nucleotide change in the c-myc internal ribosome entry segment leads to enhanced binding of a group of protein factors. 962 5

The cellular oncogene MYC and plasma cell growth, differentiation, and survival factor IL-6 play critical roles in the natural history of human plasma cell neoplasms such as multiple myeloma (MM). Myc and IL-6 also are at the center of neoplastic plasma cell transformation in BALB/c mice that carry a human IL-6 transgene and, therefore, predictably develop plasmacytomas (PCTs). We showed previously that, much like advanced MM or human myeloma cell lines (HMCLs), in which MYC is frequently deregulated in cis because of complex cytogenetic aberrations juxtaposing MYC to immunoglobulin enhancers, IL-6 transgenic PCTs commonly deregulate Myc in cis by chromosomal translocation, predominantly T(12;15)(Igh-Myc). In this article, we show that, analogous to primary MM in which MYC is mostly deregulated in trans by signaling pathways converging at the MYC promoter, IL-6 transgenic PCTs sometimes develop in the absence of Myc translocations, thus activating Myc in trans. We present cytogenetic and molecular evidence on two IL-6 transgenic PCTs that contained overexpressed Myc protein but lacked T(12;15)(Igh-Myc) and two related Myc--deregulating translocations that juxtapose Myc to immunoglobulin light-chain instead of heavy-chain enhancers: T(6;15)(Igkappa-Pvt1) and T(15;16)(Pvt1-Iglambda). We conclude that Myc translocations are not strictly required for IL-6-driven PCT development in mice. IL-6 transgenic PCTs may provide a valuable model system for elucidating both trans and cis mechanisms of Myc deregulation of great relevance for MYC deregulation in human MM.
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PMID:Extraosseous IL-6 transgenic mouse plasmacytoma sometimes lacks Myc-activating chromosomal translocation. 1575 Oct 44

Prior work indicates that c-myc translation is up-regulated in multiple myeloma cells. To test a role for interleukin (IL)-6 in myc translation, we studied the IL-6-responsive ANBL-6 and IL-6-autocrine U266 cell lines as well as primary patient samples. IL-6 increased c-myc translation, which was resistant to rapamycin, indicating a mechanism independent of mammalian target of rapamycin (mTOR) and cap-dependent translation. In contrast, the cytokine enhanced cap-independent translation via a stimulatory effect on the myc internal ribosome entry site (IRES). As known IRES-trans-activating factors (ITAF) were unaffected by IL-6, we used a yeast-three-hybrid screen to identify novel ITAFs and identified hnRNP A1 (A1) as a mediator of the IL-6 effect. A1 specifically interacted with the myc IRES in filter binding assays as well as EMSAs. Treatment of myeloma cells with IL-6 induced serine phosphorylation of A1 and increased its binding to the myc IRES in vivo in myeloma cells. Primary patient samples also showed binding between A1 and the IRES. RNA interference to knock down hnRNP A1 prevented an IL-6 increase in myc protein expression, myc IRES activity, and cell growth. These data point to hnRNP A1 as a critical regulator of c-myc translation and a potential therapeutic target in multiple myeloma.
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PMID:IL-6-induced stimulation of c-myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. 1907 89

Prior work indicates that IL-6 can stimulate c-Myc expression in multiple myeloma (MM) cells, which is independent of effects on transcription and due to enhanced translation mediated by an internal ribosome entry site in the 5'-UTR of the c-Myc RNA. The RNA-binding protein hnRNP A1 (A1) was also critical to IL-6-stimulated translation. Because A1 shuttles between nucleus and cytoplasm, we investigated whether the ability of IL-6 to enhance Myc translation was mediated by stimulation of A1 shuttling. In MM cell lines and primary specimens, IL-6 increased A1 cytoplasmic localization. In contrast, there was no effect on the total cellular levels of A1. Use of a dominant negative A1 construct, which prevents endogenous A1 from nucleus-to-cytoplasm transit, prevented the ability of IL-6 to enhance Myc internal ribosome entry site activity, Myc protein expression, and MM cell growth. IL-6-stimulated cytoplasmic localization was mediated by alterations in the C-terminal M9 peptide of A1, and this correlated with the ability of IL-6 to induce serine phosphorylation of this domain. A p38 kinase inhibitor prevented IL-6-induced A1 phosphorylation. Thus, IL-6 activates c-Myc translation in MM cells by inducing A1 phosphorylation and cytoplasmic localization in a p38-dependent fashion. These data suggest A1 as a potential therapeutic target in MM.
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PMID:IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the rna-binding protein hnRNP A1. 2097 48

When mTOR inhibitor rapalogs prevent cap-dependent translation of cell-cycle proteins like c-myc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5'-UTR (untranslated region) of transcripts. To investigate if rapalog-induced activation of MNK kinases had a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin (RAP)-activated MNK1 kinase activity in MM cell lines and primary specimens by a mitogen-activated protein kinase-dependent mechanism. Pharmacological inhibition of MNK activity or genetic silencing of MNK1 prevented a rapalog-induced upregulation of c-myc IRES activity. Although RAP, used alone, had little effect on myc protein expression, when combined with a MNK inhibitor, myc protein expression was abrogated. In contrast, there was no inhibition of myc RNA, consistent with an effect on myc translation. In a RAP-resistant MM cell lines as well as a resistant primary MM specimen, co-exposure to a MNK inhibitor or MNK1 knockdown significantly sensitized cells for RAP-induced cytoreduction. Studies in MNK-null murine embryonic fibroblasts additionally supported a role for MNK kinases in RAP-induced myc IRES stimulation. These results indicate that MNK kinase activity has a critical role in the fail-safe mechanism of IRES-dependent translation when mTOR is inhibited. As kinase activity also regulated sensitivity to RAP, the data also provide a rationale for therapeutically targeting MNK kinases for combined treatment with mTOR inhibitors.
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PMID:MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. 2237 Jun 34

Many oncogenic signals originate from abnormal protein-protein interactions that are potential targets for small molecule inhibitors. However, the therapeutic disruption of these interactions has proved elusive. We report here that the naturally-occurring triterpenoid celastrol is an inhibitor of the c-Myc (Myc) oncoprotein, which is over-expressed in many human cancers. Most Myc inhibitors prevent the association between Myc and its obligate heterodimerization partner Max via their respective bHLH-ZIP domains. In contrast, we show that celastrol binds to and alters the quaternary structure of the pre-formed dimer and abrogates its DNA binding. Celastrol contains a reactive quinone methide group that promiscuously forms Michael adducts with numerous target proteins and other free sulfhydryl-containing molecules. Interestingly, triterpenoid derivatives lacking the quinone methide showed enhanced specificity and potency against Myc. As with other Myc inhibitors, these analogs rapidly reduced the abundance of Myc protein and provoked a global energy crisis marked by ATP depletion, neutral lipid accumulation, AMP-activated protein kinase activation, cell cycle arrest and apoptosis. They also inhibited the proliferation of numerous established human cancer cell lines as well as primary myeloma explants that were otherwise resistant to JQ1, a potent indirect Myc inhibitor. N-Myc amplified neuroblastoma cells showed similar responses and, in additional, underwent neuronal differentiation. These studies indicate that certain pharmacologically undesirable properties of celastrol such as Michael adduct formation can be eliminated while increasing selectivity and potency toward Myc and N-Myc. This, together with their low in vivo toxicity, provides a strong rationale for pursuing the development of additional Myc-specific triterpenoid derivatives.
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PMID:Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids. 2647 87