Cell‐context specific role of the E2F/Rb pathway in development and disease

Swiss, Victoria A.; Casaccia, Patrizia

doi:10.1002/glia.20933

Cited by 53 publications

(53 citation statements)

References 173 publications

(251 reference statements)

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“…In addition to postnatal cell proliferation, Rb has been shown to regulate cell lineage commitment (20) and the development of various tissues (43). Here we illustrate a unique role of Rb in cell fate choice between pancreatic α-and β-cells.…”

Section: Discussionmentioning

confidence: 77%

Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate

Cai

Schroer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic endocrine cells expand rapidly during embryogenesis by neogenesis and proliferation, but during adulthood, islet cells have a very slow turnover. Disruption of murine retinoblastoma tumor suppressor protein (Rb) in mature pancreatic β-cells has a limited effect on cell proliferation. Here we show that deletion of Rb during embryogenesis in islet progenitors leads to an increase in the neurogenin 3-expressing precursor cell population, which persists in the postnatal period and is associated with increased β-cell mass in adults. In contrast, Rb-deficient islet precursors, through repression of the cell fate factor aristaless related homeobox, result in decreased α-cell mass. The opposing effect on survival of Rb-deficient α-and β-cells was a result of opposing effects on p53 in these cell types. As a consequence, loss of Rb in islet precursors led to a reduced α-to β-cell ratio, leading to improved glucose homeostasis and protection against diabetes.diabetes mellitus | insulin | glucagon | cell cycle | E2f

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Section: Discussionmentioning

confidence: 77%

Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate

Cai

Schroer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Since an obligatory relationship exists between cell cycle exit and differentiation in oligodendrocyte lineage cells (Swiss and Casaccia, 2010), and BrDis have been reported to inhibit proliferation of cancer cells, we asked whether the differential effect on differentiation observed after treatment with Olinone or MS417 could be due to a distinct modulation of the cell cycle. To address this question we adopted three different approaches including: immunohistochemistry with antibodies for the cell cycle marker Ki67 (Figure 3A), expression levels of cell cycle genes (Figure 3B) and FACS analysis (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression

Gacias

Gerona‐Navarro

Plotnikov

et al. 2014

Chemistry & Biology

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137

168

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SUMMARY Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extra-terminal domain) proteins, has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences, remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our newly designed small molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors towards differentiation, while inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target-specific, as it was not detected in cells treated with inactive analogues and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration.

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“…6d), which is consistent with the known role of Nrsf in brain development 41 . E2f targets were also enriched for functional annotations matching the known neurodevelopmental functions of the E2f family 42 (Fig. 6e).…”

Section: Npgmentioning

confidence: 99%