Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

Athineos, Dimitris; Sansom, Owen J.

doi:10.1038/onc.2010.5

Cited by 39 publications

(40 citation statements)

References 24 publications

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“…The targets of USP28 have well-characterized roles in tumor formation. c-MYC is required for neoplasia after APC inactivation, and c-JUN is required for oncogenesis in the Apc min/+ mouse model (15,16,37). Cyclin E1, a key target of c-MYC activation, is required for the chromosomal instability phe-jci.org…”

Section: Discussionmentioning

confidence: 99%

“…In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15)(16)(17)(18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

“…Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24)(25)(26)(27)(28)(29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting MYC can eliminate tumors with minimal disturbance to normal tissue (30,31).…”

Section: Introductionmentioning

confidence: 99%

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The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

127

141

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R e s e a R c h a R t i c l e3 4 0 7 jci.org Volume 124 Number 8 August 2014 IntroductionThe intestine is made up of repetitive units that consist of a differentiated compartment (the villus) and a proliferative compartment (the crypt). Intestinal stem cells are located in the crypt (1, 2) and produce rapidly proliferating daughter cells, the transit amplifying cells, which subsequently differentiate into 2 main epithelial lineages. The absorptive lineage is composed of all enterocytes, while the secretory lineage is composed of goblet cells (secreting protective mucins), enteroendocrine cells (secreting hormones like serotonin or secretin), and Paneth cells (3, 4). Whether transit amplifying cells differentiate along an absorptive or a secretory lineage is regulated by the Notch pathway (5). Engagement of Notch receptors by Notch ligands, such as Delta or Jagged, induces proteolytic cleavage of the receptor by γ-secretase. The cleaved NOTCH1 receptor (NICD1) translocates into the nucleus, resulting in the formation of an active transcriptional complex composed of RBPJκ (also known as CSL or CBF1) and NICD1. Notch signal activation induces hairy/enhancer of split (Hes) gene expression. Ablation of Notch signaling via genetic deletion of Rbpj results in secretory cell expansion (6). Conversely, in transgenic mice overexpressing NICD1, goblet cells are absent, and the proliferative compartment is expanded (7).The Wnt signaling pathway is a key regulator of intestinal stem cell homeostasis (8), and 2 of the target genes induced by Wnt signaling, c-MYC and c-JUN, encode transcription factors that have oncogenic potential (9, 10). Consequently, aberrant activation of the adenomatous polyposis coli/β-catenin/T cell factor (APC/ β-catenin/TCF) pathway is an initiating event in the majority of human colorectal cancers (11).c-MYC is a transcription factor with key functions in cell differentiation and cancer development (12)(13)(14). In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15-18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19-21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22). Thus, an E3 ubiquitin ligase and a deubiquitinase, FBW7 and USP28, are together recruited to substrates (22), and a cycle of deubiquitination and ubiquitination controls c-MYC stability.Genomic data from human cancers suggest that most colorectal cancer mutations converge on c-MYC misregulation (23). Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24-29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

127

141

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that transient overexpression of the dominant-negative Myc protein 'Omo-Myc', which is thought to prevent Myc/Max dimerization, can cause tumor regression in established lung adenomas driven by KRAS mutation (Soucek et al, 2008). We have previously shown that Apc deficiency in the mouse intestine requires Myc at the onset of hyperplasia (Athineos and Sansom, 2010;Sansom et al, 2007). Nevertheless, no studies have shown whether there is a sustained requirement for Myc in this context.…”

Section: Research Articlementioning

confidence: 99%

Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut

et al. 2012

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SUMMARYInactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia following loss of Apc in the intestine. Our results indicate that the conserved Wnt target Myc and its binding partner Max are required for the initiation and maintenance of intestinal stem cell (ISC) hyperproliferation following Apc1 loss. Importantly, we find that loss of Apc1 leads to the production of the interleukin-like ligands Upd2/3 and the EGF-like Spitz in a Myc-dependent manner. Loss of Apc1 or high Wg in ISCs results in non-cell-autonomous upregulation of upd3 in enterocytes and subsequent activation of Jak/Stat signaling in ISCs. Crucially, knocking down Jak/Stat or Spitz/Egfr signaling suppresses Apc1-dependent ISC hyperproliferation. In summary, our results uncover a novel non-cell-autonomous interplay between Wnt/Myc, Egfr and Jak/Stat signaling in the regulation of intestinal hyperproliferation. Furthermore, we present evidence suggesting potential conservation in mouse models and human CRC. Therefore, the Drosophila adult midgut proves to be a powerful genetic system to identify novel mediators of APC phenotypes in the intestine.

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“…[18][19][20][21][22][23][24][25] To identify WREs that control MYC expression in human CRC cells, we previously conducted 2 genome-wide screens to map b-catenin binding sites. 26,27 These screens found a robust b-catenin binding site 1.4-kb downstream from the MYC transcription stop site, which we showed demarcated a 600-bp WRE that overlapped a previously identified DNAse I hypersensitivity site in CRC cells.…”

Section: Introductionmentioning

confidence: 99%

A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells

Shah¹,

Rennoll

Raup‐Konsavage

et al. 2015

Cell Cycle

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Deregulated Wnt/b-catenin signaling promotes colorectal cancer (CRC) by activating expression of the c-MYC protooncogene (MYC). In the nucleus, the b-catenin transcriptional co-activator binds T-cell factor (TCF) transcription factors, and together TCF/b-catenin complexes activate MYC expression through Wnt responsive DNA regulatory elements (WREs). The MYC 3' WRE maps 1.4-kb downstream from the MYC transcription stop site and binds TCF4/b-catenin transcription complexes to activate MYC. However, the underlying mechanisms for how this element operates are not fully understood. Here, we report that the TCF family member, TCF3, plays an important role in regulating MYC expression in CRCs. We demonstrate that TCF3 binds the MYC 3 0 WRE to repress MYC. When TCF3 is depleted using shRNAs, the MYC 3 0 WRE is more available to bind TCF4/b-catenin complexes. Stimulating downstream Wnt/b-catenin signaling by inhibiting GSK3b causes an exchange of TCF3 with TCF4/b-catenin complexes to activate MYC. Finally, this transcription factor switch at the MYC 3 0 WRE controls MYC expression as quiescent cells re-enter the cell cycle and progress to S phase. These results indicate that a dynamic interplay of TCF transcription factors governs MYC gene expression in CRCs.

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Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

Cited by 39 publications

References 24 publications

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut

A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells

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