Genetics and Epigenetics of Human Retinoblastoma

Benavente, Claudia A.; Dyer, Michael A.

doi:10.1146/annurev-pathol-012414-040259

Cited by 120 publications

(80 citation statements)

References 97 publications

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“…Despite the identification of loss or inactivation of the RB1 gene as the main genetic driver responsible for the development of retinoblastoma, recent studies have suggested that additional pathways and genes are involved [31]. Here, we focused on activity of Notch in promoting growth and proliferation in retinoblastoma, since this pathway is known to play a key role in the specification and survival of stem and progenitor cells during retinal development [13].…”

Section: Discussionmentioning

confidence: 99%

Targeting Notch signaling as a novel therapy for retinoblastoma

et al. 2016

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Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma.

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Section: Discussionmentioning

confidence: 99%

Targeting Notch signaling as a novel therapy for retinoblastoma

et al. 2016

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“…The Rb gene was the first tumor suppressor gene identified and was initially linked to the formation of rare cases of pediatric tumors of the retina called retinoblastoma (21)(22)(23). Subsequent studies have identified alterations in the Rb gene or inactivation of the Rb protein in a variety of human cancers (24,25), and it is now widely accepted that the inactivation of the Rb protein may be one of the most frequent events in cancer (26).…”

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confidence: 99%

Ras Regulates Rb via NORE1A

Barnoud

Donninger²,

Clark

2016

Journal of Biological Chemistry

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Mutations in the Ras oncogene are one of the most frequent events in human cancer. Although Ras regulates numerous growth-promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene-induced senescence. Although senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major prosenescent tumor suppressor, the retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence.Ras mutations are the most frequent oncogenic events in human cancer and can be found in ϳ30% of all human cancers (1). In experimental systems, activated forms of Ras can be powerfully transforming, and transgenic animal models have validated the role of Ras activation in tumorigenesis (2, 3). However, despite the extensive evidence linking Ras to transformation and tumor development, activated Ras can also promote a state of irreversible cell cycle arrest called oncogeneinduced senescence (4, 5). This tendency for deregulated Ras activity to provoke senescence can be observed in Ras-driven tumors (6). It appears that senescence provides a potent barrier to suppress the development of Ras-driven cancer because malignant tumors lose the senescence phenotype (6). The exact mechanisms by which Ras can promote senescence are not completely understood, but it appears that the main Ras senescence pathways involve the p53 and retinoblastoma (Rb) 2 tumor suppressors (7). Initial evidence in mouse embryonic fibroblasts (MEFs) suggests that loss of functional p53 or Rb pathways alone is sufficient for Ras to bypass senescence (5). More recent studies have shown that, in vivo, suppression of p53 function (8) or Rb (9) enhances Ras-mediated transformation in murine systems. However, human systems may require inactivation of both p53 and Rb for full senescence evasion (10). Therefore, inactivation of the p53 and Rb senescence pathways may be essential for Ras-induced transformation.In addition to the classic trio of growth-promoting Ras effector proteins, Raf, PI3K, and RalGDS, Ras also interacts with growth-suppressing effector proteins, including NORE1A (RASSF5) (11,12). NORE1A is a member of the RASSF family of tumor suppressors that is frequently down-regulated during tumor development, and its inactivation has been linked to a rare familial cancer...

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“…pRB phosphorylation by cyclin-dependent kinases prevents this association, allowing cell-cycle progression (Dynlacht et al., 1994, Weinberg, 1995). However, it is now known that pRB binds numerous cofactors, and is involved in many cellular mechanisms such as apoptosis, genome stability maintenance, and differentiation (Benavente and Dyer, 2015, Burkhart and Sage, 2008, Dyson, 2016, Thomas et al., 2003). Rb1 -deficient mouse embryos exhibit substantial developmental defects in mesenchymal development, bone formation, hematopoiesis, and the nervous system (Calo et al., 2010, Jacks et al., 1992).…”

Section: Introductionmentioning

confidence: 99%

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells

et al. 2017

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SummaryHuman embryonic stem cells (hESCs) provide a platform for studying human development and understanding mechanisms underlying diseases. Retinoblastoma-1 (RB1) is a key regulator of cell cycling, of which biallelic inactivation initiates retinoblastoma, the most common congenital intraocular malignancy. We developed a model to study the role of RB1 in early development and tumor formation by generating RB1-null hESCs using CRISPR/Cas9. RB1−/− hESCs initiated extremely large teratomas, with neural expansions similar to those of trilateral retinoblastoma tumors, in which retinoblastoma is accompanied by intracranial neural tumors. Teratoma analysis further revealed a role for the transcription factor ZEB1 in RB1-mediated ectoderm differentiation. Furthermore, RB1−/− cells displayed mitochondrial dysfunction similar to poorly differentiated retinoblastomas. Screening more than 100 chemotherapies revealed an RB1–/–-specific cell sensitivity to carboplatin, exploiting their mitochondrial dysfunction. Together, our work provides a human pluripotent cell model for retinoblastoma and sheds light on developmental and tumorigenic roles of RB1.

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Genetics and Epigenetics of Human Retinoblastoma

Cited by 120 publications

References 97 publications

Targeting Notch signaling as a novel therapy for retinoblastoma

Targeting Notch signaling as a novel therapy for retinoblastoma

Ras Regulates Rb via NORE1A

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells

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