Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis

McEvoy, Justina; Flores‐Otero, Jacqueline; Zhang, Jiakun; Nemeth, Katie; Brennan, Rachel C.; Bradley, Cori; Krafcik, Fred; Rodríguez‐Galindo, Carlos; Wilson, Matthew W.; Xiong, Shunbin; Lozano, Guillermina; Sage, Julien; Fú, Ligia; Louhibi, Lotfi; Trimarchi, Jeffrey M.; Pani, Amar K.; Smeyne, Richard J.; Johnson, Dianna A.; Dyer, Michael A.

doi:10.1016/j.ccr.2011.07.005

Cited by 120 publications

(182 citation statements)

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“…It is clear that strong overexpression of MDM4 can promote retinoblastoma in mice (26), but our study reveals that most cases of increased MDM4 copy number in human retinoblastoma arise through low-level gain of the whole long arm of 1q (Supplemental Figure 2). A novel mouse model that exhibits low levels of MDM4 overexpression (27) will be an important tool to test the notion that low levels of increases in MDM4 expression (i.e., via 1q gain) may be oncogenic in retinoblastoma.…”

Section: Discussionmentioning

confidence: 71%

Cooperation between Rb and Arf in suppressing mouse retinoblastoma

Conkrite

Sundby²,

Mu³

et al. 2012

J. Clin. Invest.

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Retinoblastoma is a pediatric cancer that has served as a paradigm for tumor suppressor gene function. Retinoblastoma is initiated by RB gene mutations, but the subsequent cooperating mutational events leading to tumorigenesis are poorly characterized. We investigated what these additional genomic alterations might be using human retinoblastoma samples and mouse models. Array-based comparative genomic hybridization studies revealed deletions in the CDKN2A locus that include ARF and P16INK4A, both of which encode tumor suppressor proteins, in both human and mouse retinoblastoma. Through mouse genetic analyses, we found that Arf was the critical tumor suppressor gene in the deleted region. In mice, inactivation of one allele of Arf cooperated with Rb and p107 loss to rapidly accelerate retinoblastoma, with frequent loss of heterozygosity (LOH) at the Arf locus. Arf has been reported to exhibit p53-independent tumor suppressor roles in other systems; however, our results showed no additive effect of p53 and Arf coinactivation in promoting retinoblastoma. Moreover, p53 inactivation completely eliminated any selection for Arf LOH. Thus, our data reveal important insights into the p53 pathway in retinoblastoma and show that Arf is a key collaborator with Rb in retinoblastoma suppression.

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Section: Discussionmentioning

confidence: 71%

Cooperation between Rb and Arf in suppressing mouse retinoblastoma

Conkrite

Sundby²,

Mu³

et al. 2012

J. Clin. Invest.

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show abstract

“…This idea is consistent with the expression of progenitor cell markers in tumors (for review, see Dyer and Bremner 2005). On the other hand, coexpression of differentiated and progenitor markers within the same tumor cells (McEvoy et al 2011), the predominance of markers for more differentiated cells in human tumors (Xu et al 2009), and the demonstration that post-mitotic retinal cells can initiate tumors in mutant mice (Ajioka et al 2007) have challenged this view, and the identity of the cell of origin of retinoblastoma is still being debated. Nevertheless, loss of RB function does have visible effects in retinal progenitors.…”

Section: Retinal Progenitorsmentioning

confidence: 80%

“…Nevertheless, loss of RB function does have visible effects in retinal progenitors. For instance, deletion of the mouse Rb gene in the developing mouse retina results in ectopic proliferation and increased cell death in specific cell populations; further deletion of p107 and/or p130 enhances these defects and is required to initiate retinoblastoma in mice (Chen et al 2004;MacPherson et al 2004;McEvoy et al 2011). Inactivation of the E2f1-3 genes in mouse retinal progenitors further showed that these E2F factors, the activity of which is increased in the absence of RB, play a critical role in the survival of these progenitors-and not, surprisingly, in their capacity to proliferate Chong et al 2009).…”

Section: Retinal Progenitorsmentioning

confidence: 99%

The retinoblastoma tumor suppressor and stem cell biology

Sage¹

2012

Genes Dev.

Self Cite

107

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Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development. Basic functions of the RB pathwayThe human retinoblastoma gene RB1 was initially cloned from children with a rare form of eye cancer of the same name. Since this seminal discovery, RB has been found to be inactivated in a wide range of pediatric and adult human cancers. The mechanisms of tumor suppression by the RB protein are thought to largely involve its ability to restrict cell cycle progression at the G1/S transition of the cell cycle by inhibition of E2F transcription factors. Phosphorylation of RB by Cyclin/Cdk (cyclin-dependent kinase) complexes can inhibit the ability of RB to bind to E2F. Cyclin/Cdk complexes are themselves under the control of small cell cycle inhibitors of the INK4 and CIP/KIP families, to which p16Ink4a and p21 Cip1 , respectively, belong. The module comprising INK4-CIP/KIP cell cycle inhibitors; Cyclin/Cdk complexes; RB and its two family members, p107 and p130; and E2F transcription factors constitutes the RB pathway in cells.

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“…Indeed, basic research studies in mice are suggesting that cisplatin-resistant tumors are still sensitive to imipramine treatment [16]. An increased survival in patients with small cell lung carcinoma possibly linked to imipramine treatment might suggest this drug also in off label use in patients suffering from other tumors, including glioma, colorectal cancer and retinoblastoma, which has been suggested at least by epidemiological studies [18, 19] (see Fig. 2).…”

Section: In Patients With Cancer Think About Tricyclic Antidepressantsmentioning

confidence: 99%

Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited

Lang¹,

Walter²

2017

Neurosignals

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The depressive state has been characterised as one of elevated inflammation, changed cardiovascular parameters and a deranged metabolic situation all of which holds promise for a better understanding and handling of treatment-resistance in affective disorders as well as for future developments in treatment algorithms. In this context several biomarkers are differentially regulated by antidepressant treatment and connected to metabolic, inflammatory, cardiovascular and apoptotic components of the pathophysiology, i.e. adiponectin, apolipoprotein-B, B-type natriuretic peptide, cortisol, CRP, cysteine, homocysteine, fibrinogen, adiponectin, BMI, glycated hemoglobin A1c, leptin, interferon-gamma, high-density lipoprotein, interleukin interleukin-1alpha, -1beta, -2, -4, -5, -6, -8, -10, -12, -13, -17, insulin-like growth factor-1, low-density lipoprotein, myeloperoxidase, osteoprotegerin, tumour necrosis factor alpha, troponins, triglycerides etc. In this context antidepressants exert different modulatory effects on the outcome, incidence and mortality concerning several severe disorders, i.e. cancer, diabetes, stroke, inflammation, stroke and cardiovascular risk. Vice versa different drugs used in the treatment of these disorders have a favourable effect in depressive states, e.g. statins, aspirine, NSAIDs, pioglitazone, celecoxib, peroxisome proliferator-activated receptor-gamma agonists and minocycline. In this review, actions of different antidepressant treatment strategies on cancer, stroke, diabetes and cardiovascular disorders are shown and the influence on the outcome of the disorders is differentially discussed. In conclusion a hypothetic model for the implication of actual findings in everyday clinical practice is proposed. In this context personalized treatment could be used to tailor treatment to specific individuals according to their clinical endophenotypes. Moreover a potential target for the development of novel intervention strategies might be used.

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Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis

Cited by 120 publications

References 38 publications

Cooperation between Rb and Arf in suppressing mouse retinoblastoma

Cooperation between Rb and Arf in suppressing mouse retinoblastoma

The retinoblastoma tumor suppressor and stem cell biology

Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited

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