Activation of Transferrin Receptor 1 by c-Myc Enhances Cellular Proliferation and Tumorigenesis

O’Donnell, Kathryn A.; Yu, Duonan; Zeller, Karen; Kim, Jung-whan; Racke, Frederick; Thomas-Tikhonenko, Andrei; Dang, Chi V.

doi:10.1128/mcb.26.6.2373-2386.2006

Cited by 218 publications

(173 citation statements)

References 63 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…4 and Table S1. Doxycycline-treated cells showed strong negative enrichment for previously established gene signatures of MYC (25)(26)(27) (Table S1). Treatment of P493-6 cells with KJ-Pyr-9 also resulted in this negative enrichment of essentially the same MYC-driven transcriptional signatures.…”

Section: A Library Of Pyridine Compounds Yields Effective Inhibitors mentioning

confidence: 99%

“…To study the effect of KJ-Pyr-9 on MYC-dependent transcription, we again chose P493-6 cells, in which MYC expression can be suppressed with doxycycline. These cells have been widely used as a model system to investigate the transcriptional targets of MYC (7,(25)(26)(27). RNA sequencing (RNAseq) was performed in triplicate on untreated P493-6 cells as well as those treated separately with KJ-Pyr-9 and doxycycline to assess the effect of KJ-Pyr-9 on the transcriptional targets of MYC.…”

Section: A Library Of Pyridine Compounds Yields Effective Inhibitors mentioning

confidence: 99%

See 1 more Smart Citation

Inhibitor of MYC identified in a Kröhnke pyridine library

Hart¹,

Garner

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

131

View full text Add to dashboard Cite

In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. The K d of KJ-Pyr-9 for MYC in vitro is 6.5 ± 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.M YC is a transcriptional regulator that occupies an apex position in the organizational hierarchy of the cell (1-3). It belongs to a family of basic helix-loop-helix leucine zipper (bHLH-LZ) proteins that dimerize with the small bHLH-LZ protein MAX to become functional (4). The MYC-MAX heterodimer preferentially binds to the palindromic DNA sequence CACGTG, referred to as the E-box motif. As a transcription factor, MYC can bind to the promoters of target genes to stimulate or repress transcriptional activity (5-7). The human genome contains three MYC genes, c-MYC, N-MYC, and L-MYC. Throughout this paper, we will use "MYC" to indicate the protein product of the c-MYC gene.MYC is involved in almost all cancers (8, 9). It is rarely mutated, but achieves gain of function through overexpression or amplification. Because of this broad pathogenic significance, MYC is an important cancer target. However, both conceptual and practical difficulties have stood in the way of identifying potent and effective small-molecule inhibitors of MYC. The conceptual obstacles reflect concern about inhibiting a gene that controls essential cellular activities. Because MYC plays an important role in cell proliferation (10, 11), it is often argued that inhibition of this function would lead to broad and unacceptable side effects in vivo. However, studies with the dominant-negative MYC construct Omomyc have shown that inhibiting MYC has only mild and rapidly reversible effects on normal, fast-proliferating tissues (8,12,13). The main practical difficulty in targeting MYC is the absence of pockets or grooves that could serve as binding sites for small molecules (14).The preferred strategy for the identification of potential MYC inhibitors has been interference with MYC-MAX dimerization (15-18). The formation of the MYC-MAX heterodimer involves the bHLH-LZ domains of the two partner molecules with a protein-protein interaction (PPI) surface of ∼3,200 Å 2 . This surface lacks well-defined binding sites for small molecules and therefore is widely considered as "undruggable." However, despite the large interaction surface, a single-amino acid substitution can completely disrupt the dimerization of MYC with MAX (14...

show abstract

Section: A Library Of Pyridine Compounds Yields Effective Inhibitors mentioning

confidence: 99%

Section: A Library Of Pyridine Compounds Yields Effective Inhibitors mentioning

confidence: 99%

Inhibitor of MYC identified in a Kröhnke pyridine library

Hart¹,

Garner

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

131

View full text Add to dashboard Cite

show abstract

“…Several direct Myc targets have been well defined (Dang, 1999;Grandori et al, 2000;Hermeking et al, 2000;Eisenman, 2001;Patel et al, 2004), most of them with biological functions in cell cycle control, metabolism or ribosome biogenesis, but only a few have so far been directly linked to the transforming function of Myc (Eisenman, 2001, Patel et al, 2004. These include the ornithine decarboxylase gene (ODC), the tumor-associated membrane glycoprotein gene Tmp, the metastasis-associated protein 1 (MTA1) gene, or the transferrin receptor 1 (TFRC1) gene, that were shown to have oncogenic potential (BenPorath et al, 1999;Eisenman, 2001;Zhang et al, 2005;O'Donnell et al, 2006). However, none of these genes can fully substitute for myc function.…”

Section: Ws5 a Direct Transcriptional Target Of Myc F Reiter Et Almentioning

confidence: 99%

“…Also, an important unresolved question is whether deregulated oncogenic Myc promotes tumorigenesis by aberrant regulation of its normal targets or by affecting new ones. Several Myc targets have recently been identified that display partial oncogenic potential (Ben-Porath et al, 1999;Zhang et al, 2005;O'Donnell et al, 2006). Notably, no target gene has been identified so far that can mimic the full oncogenic capacity of myc upon ectopic expression, supporting the notion that the molecular events downstream of myc represent a multifunctional response.…”

Section: Introductionmentioning

confidence: 97%

WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential

et al. 2006

View full text Add to dashboard Cite

We have isolated a gene (WS5) that is specifically expressed at the mRNA and protein level in avian fibroblasts transformed by the v-myc oncogene of avian acute leukemia virus MC29. In a conditional cell transformation system, WS5 gene expression was tightly correlated with v-myc activation. The WS5 gene contains 11 exons, encoding a 733-amino acid protein with a transmembrane region and a polycystic kidney disease (PKD) domain. Near the transcriptional start site, the WS5 promoter contains a cluster of four binding sites for the Myc-Max complex and a binding site for transcription factor C/EBPa. Electrophoretic mobility shift assays and chromatin immunoprecipitation showed that Myc, Max and C/EBPa bind specifically to these sites. Functional promoter analyses revealed that both the Myc-binding site cluster and the C/EBPa-binding site are essential for strong transcriptional activation, and that Myc and C/EBPa synergistically activate the WS5 promoter. Ectopic expression of WS5 led to cell transformation documented by anchorage-independent growth. The human melanoma antigen Pmel17, a type I transmembrane glycoprotein, is the mammalian protein with the highest amino acid sequence identity (38%) to WS5. The Pmel17 gene is regulated by the MITF protein, a bHLHZip transcription factor with DNA binding specificities similar to those of Myc/Max. WS5 is also related to human glycoprotein GPNMB expressed in metastatic melanoma cells and implicated in the progression of brain and liver tumors.

show abstract

“…5E,F ;O'Donnell et al 2006), leading to an increase in steady-state protein levels. By using 89 Zr-desferrioxamine-labeled transferrin ( 89 Zr-transferrin), a new positron emission tomography (PET) radiotracer that binds TFRC (Holland et al 2012), it is possible to indirectly assess MYC activity in vivo.…”

Section: Cdk9 Mediates Transcription Elongation Of Myc Targets In Mycmentioning

confidence: 99%

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

et al. 2014

View full text Add to dashboard Cite

One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.

show abstract

Activation of Transferrin Receptor 1 by c-Myc Enhances Cellular Proliferation and Tumorigenesis

Cited by 218 publications

References 63 publications

Inhibitor of MYC identified in a Kröhnke pyridine library

Inhibitor of MYC identified in a Kröhnke pyridine library

WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

Contact Info

Product

Resources

About