Journal article
The tumor suppressor gene Trp53 protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens
Disease models & mechanisms, Vol.4(4), pp.484-495
07/2011
DOI: 10.1242/dmm.006593
PMCID: PMC3124053
PMID: 21504908
Abstract
We previously found that lenses lacking the Acvr1 gene, which encodes a bone morphogenetic protein (BMP) receptor, had abnormal proliferation and cell death in epithelial and cortical fiber cells. We tested whether the tumor suppressor protein p53 (encoded by Trp53) affected this phenotype. Acvr1 conditional knockout (Acvr1(CKO)) mouse fiber cells had increased numbers of nuclei that stained for p53 phosphorylated on serine 15, an indicator of p53 stabilization and activation. Deletion of Trp53 rescued the Acvr1(CKO) cell death phenotype in embryos and reduced Acvr1-dependent apoptosis in postnatal lenses. However, deletion of Trp53 alone increased the number of fiber cells that failed to withdraw from the cell cycle. Trp53(CKO) and Acvr1;Trp53(DCKO) (double conditional knockout), but not Acvr1(CKO), lenses developed abnormal collections of cells at the posterior of the lens that resembled posterior subcapsular cataracts. Cells from human posterior subcapsular cataracts had morphological and molecular characteristics similar to the cells at the posterior of mouse lenses lacking Trp53. In Trp53(CKO) lenses, cells in the posterior plaques did not proliferate but, in Acvr1;Trp53(DCKO) lenses, many cells in the posterior plaques continued to proliferate, eventually forming vascularized tumor-like masses at the posterior of the lens. We conclude that p53 protects the lens against posterior subcapsular cataract formation by suppressing the proliferation of fiber cells and promoting the death of any fiber cells that enter the cell cycle. Acvr1 acts as a tumor suppressor in the lens. Enhancing p53 function in the lens could contribute to the prevention of steroid- and radiation-induced posterior subcapsular cataracts.
Details
- Title: Subtitle
- The tumor suppressor gene Trp53 protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens
- Creators
- Luke A Wiley - Department of Ophthalmology and Visual Sciences, Washington University, Saint Louis, MO 63110, USARamya RajagopalLisa K DattiloDavid C Beebe
- Resource Type
- Journal article
- Publication Details
- Disease models & mechanisms, Vol.4(4), pp.484-495
- DOI
- 10.1242/dmm.006593
- PMID
- 21504908
- PMCID
- PMC3124053
- NLM abbreviation
- Dis Model Mech
- ISSN
- 1754-8411
- eISSN
- 1754-8411
- Publisher
- England
- Grant note
- T32 HL007873 / NHLBI NIH HHS P30 EY002687 / NEI NIH HHS 2 T32 HL007873 / NHLBI NIH HHS R01 EY004853 / NEI NIH HHS EY04853 / NEI NIH HHS EY002687 / NEI NIH HHS
- Language
- English
- Date published
- 07/2011
- Academic Unit
- Ophthalmology and Visual Sciences
- Record Identifier
- 9983980079302771
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