The tumor suppressor geneTrp53protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens

Abstract

SUMMARYWe 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 (Acvr1CKO) 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 Acvr1CKO 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. Trp53CKO and Acvr1;Trp53DCKO (double conditional knockout), but not Acvr1CKO, 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 Trp53CKO lenses, cells in the posterior plaques did not proliferate but, in Acvr1;Trp53DCKO 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.

Aberrant activation of p53 due to loss of MDM2 or MDMX causes early lens dysmorphogenesis

“…Deficiency of some genes required for normal lens development, such as OREBP and Ncoa6, induces DNA strand breaks and cell cycle arrest, resulting in incomplete elongation and differentiation of lens fiber cells and nuclear cataract, due to the activation of p53 (Wang et al, 2010; Wang et al, 2005). On the other hand, lack of p53 in lens leads to the accumulation of the fiber cells in the posterior plaques, and then the fiber cells continue to proliferate and fail to withdraw from the cell cycle to form proper terminal differentiated fiber cells (Wiley et al, 2011). Consistently, p53 may play a role in preventing the formation of steroid- or radiation-induced posterior subcapsular cataracts by suppressing the improper proliferation of fiber cells and promoting the death of the fiber cells that enter the cell cycle (Wiley et al, 2011).…”

“…On the other hand, lack of p53 in lens leads to the accumulation of the fiber cells in the posterior plaques, and then the fiber cells continue to proliferate and fail to withdraw from the cell cycle to form proper terminal differentiated fiber cells (Wiley et al, 2011). Consistently, p53 may play a role in preventing the formation of steroid- or radiation-induced posterior subcapsular cataracts by suppressing the improper proliferation of fiber cells and promoting the death of the fiber cells that enter the cell cycle (Wiley et al, 2011). Besides the cataracts, over-activated p53 and subsequent apoptosis of LECs have also been suggested to be associated with microphthalmia/anophthalmia caused by some genetic deficiency (Hettmann et al, 2000; Jaramillo-Rangel et al, 2013).…”

“…Genetic studies have shown that p53 is not essential for normal embryonic development (Donehower et al, 1992; Jacks et al, 1994). However, mice with inactive or deficient p53 displayed incomplete lens fiber cell denucleation (Jean et al, 1998; Pan and Griep, 1994; Wiley et al, 2011), and failed to induce the regression of the primary vitreous during eye development (Reichel et al, 1998), resulting in a high frequency of cataracts. Likewise, abnormal induction of apoptosis in lens epithelial cells promotes the cataractogenesis caused by oxidative stress (Mok et al, 2014), UV irradiation (Ayala et al, 2007; Godar, 1996; Xiao et al, 2012), diabetes (Takamura et al, 2003; Ye et al, 2013) and aging (Zheng and Lu, 2011), which could be p53-dependent (Yan et al, 2006).…”

Transforming Growth Factor β Superfamily Signaling in Development of Colorectal Cancer

“…To date, there are no studies investigating activin signaling, either on the ligand or receptor level, in models of sporadic CRC, despite the availability of conditional models. 139,140 …”

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

“…SWI/SNF complexes are known to be recruited to phosphorylated H2AX via the interaction between the Brg1 bromodomain and acetylated lysines in histone tails (Lee et al, 2010). Studies of the canonical DNA repair protein Nbs1 (nibrin) in lens (Park et al, 2006), DNA repairassociated proteins Ddb1 (Cang et al, 2006) and Ncoa6 , the identification of DNA repair foci in lens fiber cell chromatin through phosphorylated H2AX outside of the OFZ , and the retention of nuclei in p53 (Trp53) null lenses (Wiley et al, 2011), raise the intriguing possibility that specific components of the DNA repair machinery participate in some aspects of this process using their 'non-canonical' activities adopted for the lens environment. Finally, it is possible that Brg1-and Snf2h-containing complexes assist in chromatin degradation in parallel with DNase IIβ.…”