Article

Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY 10021, USA.
Cell (Impact Factor: 33.12). 07/2009; 137(6):1018-31. DOI: 10.1016/j.cell.2009.03.051
Source: PubMed

ABSTRACT Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRgamma transcription factor and a human-specific RXRgamma consensus binding site, and proliferation required RXRgamma, as well as the cone-specific thyroid hormone receptor-beta2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.

0 Followers
 · 
158 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine whether the degree of tumor anaplasia has prognostic value by evaluating its correlation with high-risk histopathologic features and clinical outcomes in a series of retinoblastoma patients. Retrospective clinicopathologic study. The clinical and pathologic findings in 266 patients who underwent primary enucleation for retinoblastoma were reviewed. The histologic degree of anaplasia was graded as retinocytoma, mild, moderate, or severe as defined by increasing cellular pleomorphism, number of mitoses, nuclear size, and nuclear hyperchromatism. Nuclear morphometric characteristics were measured. The clinical and pathologic data of 125 patients were compared using Kaplan-Meier estimates of survival. Fisher's exact test and multivariate regression were used to analyze the association between anaplasia grade and high-risk histologic features. Increasing grade of anaplasia was associated with decreased overall survival (p=0.003) and increased risk of metastasis (p=0.0007). Histopathologic features that were associated with anaplasia included optic nerve invasion (p<0.0001), choroidal invasion (p=<0.0001), and anterior segment invasion (p=0.04). Multivariate analysis considering high-risk histopathology and anaplasia grading as predictors of distant metastasis and death showed that high-risk histopathology was statistically significant as an independent predictor (p=0.01 for metastasis, p=0.03 for death) but anaplasia was not (p=0.63 for metastasis, p=0.30 for death). In the absence of high-risk features, however, severe anaplasia identified an additional risk for metastasis (p=0.0004) and death (p=0.01). Grading of anaplasia may be a useful adjunct to standard histopathologic criteria in identifying retinoblastoma patients who do not have high-risk histologic features but still have an increased risk of metastasis and may need adjuvant therapy. Copyright © 2014 Elsevier Inc. All rights reserved.
    American Journal of Ophthalmology 12/2014; 159(4). DOI:10.1016/j.ajo.2014.12.014 · 4.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rb1 is the most frequently mutated gene in the pediatric cancer retinoblastoma, and its loss causes E2F transcription factors to induce proliferation related genes. However, high E2F levels following pRB loss also induce apoptosis-promoting genes as a safeguard mechanism to suppress emergent tumors. Although p53 accumulation and apoptosis induction is believed to be a primary mechanism to eliminate cells with excess E2F activity, p53 deletion doesn't suppress RB/E2F induced apoptosis in vivo in the retina. This prompted us to test the PTEN/PI3K/AKT signaling pathway on RB/E2F apoptosis suppression in vivo, to ascertain if the PI3K pathway may provide a potential avenue for retinoblastoma therapy. We developed a mouse model in which Rb1 and Pten were conditionally deleted from retinal progenitor cells using Chx10-Cre, whereas Rbl1 (p107) was constitutively deleted. Pathway components were also tested individually by in vivo electroporation into newborn retinas for an effect on apoptosis and tumor initiation. Mouse retinal tissues were analyzed by immunohistochemistry (IHC) for proliferation, apoptosis, and pathway activation. ShRNAs were used in vitro to assess effects on apoptosis and gene expression. Co-deleting Pten with Rb1 and Rbl1 in mouse retinal progenitor cells (RPCs) causes fully penetrant bilateral retinoblastomas by 30 days and strongly suppresses Rb/E2F-induced apoptosis. In vivo electroporation of constitutively active (ca)-Pik3ca, ca-Akt, or dominant-negative (dn)-Foxo1 into apoptosis prone newborn murine retina with deleted Rb/p107 eliminate Rb/E2F induced apoptosis and induce retinoblastoma emergence. Retinal deletion of Pten activates p-AKT and p-FOXO1 signaling in incipient retinoblastoma. An unbiased shRNA screen focusing on Akt phosphorylation targets identified FOXOs as critical mediators of Rb/E2F induced apoptosis and expression of Bim and p73 pro-apoptotic genes. These data indicate that we defined a key molecular trigger involving E2F/FOXO functioning to control retinal progenitor cell homeostasis and retinoblastoma tumor initiation. We anticipate that our findings could provide contextual understanding of the proliferation of other progenitor cells, considering the high frequency of co-altered signaling from RB/E2F and PTEN/PI3K/AKT pathways in a wide variety of normal and malignant settings.
    Molecular Cancer 04/2015; 14(1):93. DOI:10.1186/s12943-015-0360-y · 5.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many types of human cancers overexpress MDM2 protein. A common characteristic among these cancers is an associated increase in mdm2 splice variants. Provided here is a comprehensive list, based on a literature review, of over 70 mdm2 variants. These variants are grouped according to in-frame versus out-of-frame status and their potential (or ability) to be translated into isoform proteins. We describe the putative functions for these mdm2 splice variant mRNAs, as well as the mechanistic drivers associated with increased mdm2 transcription and splicing. The paradoxical signal transduction functions of the most commonly studied variants mdm2-a,-b and -c are addressed for their outcomes in the presence and absence of wild-type p53. These outcomes vary from tumor promotion to growth arrest. Finally, we present issues in the detection of endogenous MDM2 protein and how many of the antibodies commonly used to detect MDM2 do not present a full picture of the cellular representation of the isoform proteins. This review provides a focusing lens for individuals interested in learning about the complexities of mdm2 mRNAs and their protein isoforms as well as the roles MDM2 isoforms may play in cancer progression.
    Sub-cellular biochemistry 01/2014; 85:247-261. DOI:10.1007/978-94-017-9211-0_14