ArticleMolecular cancer2015
Co-deleting Pten with Rb in retinal progenitor cells in mice results in fully penetrant bilateral retinoblastomas.
Article in Molecular cancer, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 36 citations in OpenAlex.
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- The role of chance in cancer causation.La Medicina del lavoro · 2022Article
- UHRF2 regulates cell cycle, epigenetics and gene expression to control the timing of retinal progenitor and ganglion cell differentiation.Development (Cambridge, England) · 2022Article
- The emerging potentials of lncRNA DRAIC in human cancers.Frontiers in oncology · 2022Review
- Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity.Cancer cell · 2021Article
- Retinoblastoma tumor cell proliferation is negatively associated with an immune gene expression signature and increased immune cells.Laboratory investigation; a journal of technical methods and pathology · 2021Article
- Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells.PLoS genetics · 2021Article
- MicroRNA-351 Promotes the Proliferation and Invasion of Glioma Cells through Downregulation of NAIF1.Journal of molecular neuroscience : MN · 2020Article
- Retinoblastoma: Etiology, Modeling, and Treatment.Cancers · 2020Review
- miR-494 promotes progression of retinoblastoma via PTEN through PI3K/AKT signaling pathway.Oncology letters · 2020Article
- Regulating tumor suppressor genes: post-translational modifications.Signal transduction and targeted therapy · 2020Review
- LncRNA CANT1 suppresses retinoblastoma progression by repellinghistone methyltransferase in PI3Kγ promoter.Cell death & disease · 2020Article
- RRS1 Promotes Retinoblastoma Cell Proliferation and Invasion via Activating the AKT/mTOR Signaling Pathway.BioMed research international · 2020Article
- Identification of microRNA-mRNA regulatory networks and pathways related to retinoblastoma across human and mouse.International journal of ophthalmology · 2020Article
- Long non-coding RNA T-cell leukemia/lymphoma 6 serves as a sponge for miR-21 modulating the cell proliferation of retinoblastoma through PTEN.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2019Article
- HDAC5 promotes optic nerve regeneration by activating the mTOR pathway.Experimental neurology · 2019Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundRb1 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.
methodsWe 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.
resultsCo-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.
conclusionsThese 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.
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