Rapid Loss of Intestinal Crypts upon Conditional Deletion of the Wnt/Tcf-4 Target Gene c-<i>Myc</i>

Muncan, Vanesa; Sansom, Owen J.; Tertoolen, Leon G.J.; Phesse, Toby J.; Begthel, Harry; Sancho, Elena; Cole, Alicia M.; Gregorieff, Alex; Alborán, Ignacio Moreno de; Clevers, Hans; Clarke, Alan R.

doi:10.1128/mcb.00821-06

Cited by 226 publications

(211 citation statements)

References 47 publications

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“…Outbred male mice from 6 -12 weeks of age were used, and they were segregating for the C57BLJ and S129 genomes. The alleles used were as follows: Apc 580S (10), Myc fl (26), Catnb tm2Kem (12), and AhCre (12). Cre activity was induced in control and experimental mice by three i.p.…”

Section: Methodsmentioning

confidence: 99%

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver

Reed

Athineos

Méniel

et al. 2008

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

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Dysregulated Wnt signaling is seen in approximately 30% of hepatocellular carcinomas; thus, finding pathways downstream of the activation of Wnt signaling is key. Here, using cre-lox technology, we deleted the Apc gene in the adult mouse liver and observed a rapid increase in nuclear β-catenin and c-Myc, which is associated with an induction of proliferation that led to hepatomegaly within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes, we analyzed the impact of inactivating APC in the context of deficiency of the potentially key effectors β-catenin and c-Myc. β-catenin loss rescues both the proliferation and hepatomegaly phenotypes after APC loss. However, c-Myc deletion, which rescues the phenotypes of APC loss in the intestine, had no effect on the phenotypes of APC loss in the liver. The consequences of the deregulation of the Wnt pathway within the liver are therefore strikingly different from those observed within the intestine, with the vast majority of Wnt targets being β-catenin-dependent but c-Myc-independent in the liver.

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Section: Methodsmentioning

confidence: 99%

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver

Reed

Athineos

Méniel

et al. 2008

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

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“…However, at least in mice, Myc is dispensable for development until E11.5 with the exception of the hematopoietic lineage (27). Furthermore, although Myc is expressed in the proliferating compartment of several adult tissues, the postnatal deletion of Myc in mice does not result in prominent proliferation defects (25,26,28,29). These results suggest that MYC is more important for growth of tumors and cultured cells than growth and homeostasis of normal tissues.…”

Section: Difference Between Growth Control In Normal Tissues and In Cmentioning

confidence: 99%

“…As Myc is not required in the adult for most normal proliferation (25)(26)(27)(28)(29), it is likely that the biologic role of Myc and the 8q24 risk region has more to do with tissue repair and/or other responses that require temporary increase in cellular proliferation rate.…”

Section: Normal Functions Of the Regulatory Elements At 8q24mentioning

confidence: 99%

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur

Tuupanen²,

Whitington

et al. 2013

Cancer Research

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Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.

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“…In addition, the vital role of this pathway in tumorigenesis arouses great research interest (9)(10)(11). b-Catenin, stabilized by activation of WNT signaling, is translocated into the nucleus to form nuclear complexes with transcription factors of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family and subsequently activates several downstream effectors such as C-MYC and cyclin D1.…”

Section: Introductionmentioning

confidence: 99%

SPINDLIN1 Promotes Cancer Cell Proliferation through Activation of WNT/TCF-4 Signaling

Wang¹,

Zeng²,

Chen³

et al. 2012

Molecular Cancer Research

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SPINDLIN1, a new member of the SPIN/SSTY gene family, was first identified as a gene highly expressed in ovarian cancer cells. We have previously shown that it is involved in the process of spindle organization and chromosomal stability and plays a role in the development of cancer. Nevertheless, the mechanisms underlying its oncogenic role are still largely unknown. Here, we first showed that expression of SPINDLIN1 is upregulated in clinical tumors. Ectopic expression of SPINDLIN1 promoted cancer cell proliferation and activated WNT/T-cell factor (TCF)-4 signaling. The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function. Collectively, these results suggest that SPINDLIN1, which may be a novel substrate of the Aurora-A kinase, promotes cancer cell growth through WNT/ TCF-4 signaling activation. Mol Cancer Res; 10(3); 326-35. Ó2012 AACR.

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Rapid Loss of Intestinal Crypts upon Conditional Deletion of the Wnt/Tcf-4 Target Gene c-Myc

Cited by 226 publications

References 47 publications

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver

B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver

Lessons from Functional Analysis of Genome-Wide Association Studies

SPINDLIN1 Promotes Cancer Cell Proliferation through Activation of WNT/TCF-4 Signaling

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