Inhibition of Intestinal Polyposis with Reduced Angiogenesis in <i>Apc</i>Min/+ Mice Due to Decreases in c-Myc Expression

Yekkala, Krishna; Baudino, Troy A.

doi:10.1158/1541-7786.mcr-07-0232

Cited by 60 publications

(55 citation statements)

References 28 publications

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“…Min/+ mice remain undefined, we observed changes in the expression of a number of -catenin-driven genes in non-involved intestine ex vivo, including Myc, which is known to be essential for tumor formation in this model (Ignatenko et al, 2006;Yekkala and Baudino, 2007). We also observed a proportionally larger number of small adenomas in Krit1 +/-Apc Min/+ mice (Fig.…”

Section: Apcmentioning

confidence: 54%

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Glading

Ginsberg

2010

Disease Models &Amp; Mechanisms

109

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SUMMARYKRIT1, also called CCM1, is a member of a multiprotein complex that contains the products of the CCM2 and PDCD10 (also known as CCM3) loci. Heterozygous loss of any of the genes that encode these proteins leads to cerebral cavernous malformations (CCM), which are vascular lesions that are found in around 0.5% of humans. KRIT1 mediates the stabilization of -catenin-containing endothelial cell-cell junctions downstream of the Rap1 GTPase. Here, we report that Rap1 and KRIT1 are negative regulators of canonical -catenin signaling in mice and that hemizygous Krit1 deficiency exacerbates -catenin-driven pathologies. Depletion of endothelial KRIT1 caused -catenin to dissociate from vascular endothelial (VE)-cadherin and to accumulate in the nucleus with consequent increases in -catenin-dependent transcription. Activation of Rap1 inhibited -catenindependent transcription in confluent endothelial cells; this effect required the presence of intact cell-cell junctions and KRIT1. These effects of KRIT1 were not limited to endothelial cells; the KRIT1 protein was expressed widely and its depletion increased -catenin signaling in epithelial cells. Moreover, a reduction in KRIT1 expression also increased -catenin signaling in vivo. Hemizygous deficiency of Krit1 resulted in a ~1.5-fold increase in intestinal polyps in the Apc Min/+ mouse, which was associated with increased -catenin-driven transcription. Thus, KRIT1 regulates -catenin signaling,and Krit1 +/-mice are more susceptible to -catenin-driven intestinal adenomas.

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Section: Apcmentioning

confidence: 54%

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Glading

Ginsberg

2010

Disease Models &Amp; Mechanisms

109

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“…This possibility is already well-supported in the literature as both haploinsufficiency for c-Myc and complete loss of c-Myc modifies intestinal tumor formation in Apc Min/+ mice (26,27). It is interesting to note that genetic knockout of the C-Myc target genes MIF (28) or TIAM1 (16) slows adenoma formation in the Apc Min/+ mouse, and further investigation of CMyc-dependent target genes after Apc loss may identify numerous other modifiers of intestinal tumorigenesis.…”

Section: Implications and Questions Raisedmentioning

confidence: 67%

C-Myc Is a Critical Mediator of the Phenotypes of Apc Loss in the Intestine

Wilkins

Sansom

2008

Cancer Research

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The Adenomatous polyposis coli (Apc) gene is mutated in up to 80% of sporadic colorectal cancers. After Apc loss, there is deregulation of the Wnt signaling pathway and transactivation of T-cell factor/leukemia enhancing factor target genes such as C-Myc. This review focuses on recent data highlighting the importance of the C-Myc oncogene and its transcriptional targets in establishing all of the phenotypes caused by the deletion of the Apc tumor suppressor gene within the intestinal epithelium. The importance of investigating Apc and C-Myc gene function in the correct tissue context is also discussed. [Cancer Res 2008;68(13):4963-6]

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“…The importance of c-MYC in the initiation and progression of colorectal cancer was demonstrated by in vitro studies where knockdown of c-MYC inhibits the growth of colon cancer cell lines (27,28) and confirmed by studies of the mouse intestine, in which the pro-proliferative phenotype induced by APC inactivation was rescued by parallel inactivation of c-MYC (29)(30)(31).…”

Section: Introductionmentioning

confidence: 90%

Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells

Tögel

Nightingale

Chüeh

et al. 2016

Molecular Cancer Therapeutics

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Inhibitors of the bromodomain and extraterminal domain (BET) protein family attenuate the proliferation of several tumor cell lines. These effects are mediated, at least in part, through repression of c-MYC. In colorectal cancer, overexpression of c-MYC due to hyperactive WNT/b-catenin/TCF signaling is a key driver of tumor progression; however, effective strategies to target this oncogene remain elusive. Here, we investigated the effect of

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Inhibition of Intestinal Polyposis with Reduced Angiogenesis in ApcMin/+ Mice Due to Decreases in c-Myc Expression

Cited by 60 publications

References 28 publications

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

C-Myc Is a Critical Mediator of the Phenotypes of Apc Loss in the Intestine

Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells

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