Journal article
p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia
The Journal of clinical investigation, Vol.127(12), pp.4462-4476
12/01/2017
DOI: 10.1172/JCI77217
PMCID: PMC5707165
PMID: 29130932
Abstract
p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3-dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly assess the tumorigenic impact of p120 haploinsufficiency relative to other candidate drivers. Remarkably, p120 ranked third among the 919 drivers identified. Cofactors α-catenin and epithelial cadherin (E-cadherin) were also among the highest scoring candidates, indicating a mechanism at the level of the intact complex that may play an important role at very early stages of of intestinal tumorigenesis while simultaneously restricting outright loss via synthetic lethality.
Details
- Title: Subtitle
- p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia
- Creators
- Sarah P Short - Department of Cancer Biology, andJumpei Kondo - Vanderbilt UniversityWhitney G Smalley-Freed - Department of Cancer Biology, andHaruna Takeda - Kanazawa Medical UniversityMichael R Dohn - Vanderbilt UniversityAnne E Powell - Vanderbilt UniversityRobert H Carnahan - Department of Cancer Biology, andMary K Washington - Vanderbilt University Medical CenterManish Tripathi - Department of Cancer Biology, andD Michael Payne - Chulalongkorn UniversityNancy A Jenkins - Houston MethodistNeal G Copeland - Houston MethodistRobert J Coffey - Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USAAlbert B Reynolds - Department of Cancer Biology, and
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.127(12), pp.4462-4476
- DOI
- 10.1172/JCI77217
- PMID
- 29130932
- PMCID
- PMC5707165
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- P50 CA095103 / NCI NIH HHS R01 CA111947 / NCI NIH HHS R01 CA046413 / NCI NIH HHS T32 CA009592 / NCI NIH HHS R01 CA055724 / NCI NIH HHS F31 CA165667 / NCI NIH HHS
- Language
- English
- Date published
- 12/01/2017
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420941702771
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