The Retinoblastoma Protein Is Essential for Survival of Postmitotic Neurons

Andrusiak, Matthew G.; Vandenbosch, Renaud; Park, David; Slack, Ruth S.

doi:10.1523/jneurosci.1912-12.2012

Cited by 43 publications

(58 citation statements)

References 32 publications

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“…The differential regulation of proapoptotic versus cell cycle-related targets may be specific to neurons, in line with a previous report. 47 On the whole, these data show that Notch signaling positively regulates the Akt/Ccnd1 axis leading to cell cycle-related gene expression (Figure 5c). …”

Section: Discussionmentioning

confidence: 79%

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

et al. 2015

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Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.

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Section: Discussionmentioning

confidence: 79%

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

et al. 2015

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“…The massive neuronal loss in developing nervous system with Rb germline loss-of-function mutations can be explained by placental formation defects (de Bruin et al 2003). However, acute murine knockout models of Rb in terminally differentiated neurons in vitro and in vivo reported that acute inactivation of Rb in postmitotic neurons results in ectopic cell cycle protein expression and neuronal loss without concurrent induction of classical E2f-mediated apoptotic genes, such as Apaf1 (Andrusiak et al 2012). These results suggest that terminally differentiated neurons require Rb for continuous cell cycle repression and survival.…”

Section: Rb Functionsmentioning

confidence: 99%

The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB

Delou

Biasoli

Borges

2016

An. Acad. Bras. Ciênc.

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Physiological processes, as autophagy, proliferation and apoptosis are affected during carcinogenesis.Restoring cellular sensitivity to apoptotic stimuli, such as the antineoplastic cocktails, has been explored as a strategy to eliminate cancer cells. Autophagy, a physiological process of recycling organelles and macromolecules can be deviated from homeostasis to support cancer cells survival, proliferation, escape from apoptosis, and therapy resistance. The relationship between autophagy and apoptosis is complex and many stimuli can induce both processes. Most chemotherapeutic agents induce autophagy and it is not clear whether and how this chemotherapy-induced autophagy might contribute to resistance to apoptosis. Here, we review current strategies to sensitize cancer cells by interfering with autophagy. Moreover, we discuss a new link between autophagy and apoptosis: the tumor suppressor retinoblastoma protein (RB). Inactivation of RB is one of the earliest and more frequent hallmarks of cancer transformation, known to control cell cycle progression and apoptosis. Therefore, understanding RB functions in controlling cell fate is essential for an effective translation of RB status in cancer samples to the clinical outcome.

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“…Differentiating cortical neurons survive and proliferate when Rb is conditionally deleted before the start of cortical development (Ferguson et al, 2002;MacPherson et al, 2003). In adults, the acute inactivation of Rb in mature cortical neurons results in neuronal loss, demonstrating that Rb is essential for the survival of mature cortical neurons (Andrusiak et al, 2012). Although these studies clearly demonstrated that Rb-deficient differentiating cortical neurons, but not adult mature cortical neurons, escape cell death after S-phase re-entry, acute Rb inactivation in cortical differentiating neurons is inevitable for elucidating whether differentiating cortical neurons retain their proliferative potency after neurogenesis or whether the Rb-deficient primordium of the cerebral cortex generates proliferative differentiating neurons because of the context-specific roles of Rb.…”

Section: Introductionmentioning

confidence: 99%

Cortical excitatory neurons become protected from cell division during neurogenesis in an Rb family-dependent manner

et al. 2013

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SUMMARYCell cycle dysregulation leads to abnormal proliferation and cell death in a context-specific manner. Cell cycle progression driven via the Rb pathway forces neurons to undergo S-phase, resulting in cell death associated with the progression of neuronal degeneration. Nevertheless, some Rb-and Rb family (Rb, p107 and p130)-deficient differentiating neurons can proliferate and form tumors. Here, we found in mouse that differentiating cerebral cortical excitatory neurons underwent S-phase progression but not cell division after acute Rb family inactivation in differentiating neurons. However, the differentiating neurons underwent cell division and proliferated when Rb family members were inactivated in cortical progenitors. Differentiating neurons generated from Rb-/-(Rb-TKO) progenitors, but not acutely inactivated Rb-TKO differentiating neurons, activated the DNA double-strand break (DSB) repair pathway without increasing trimethylation at lysine 20 of histone H4 (H4K20), which has a role in protection against DNA damage. The activation of the DSB repair pathway was essential for the cell division of Rb-TKO differentiating neurons. These results suggest that newly born cortical neurons from progenitors become epigenetically protected from DNA damage and cell division in an Rb family-dependent manner.

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The Retinoblastoma Protein Is Essential for Survival of Postmitotic Neurons

Cited by 43 publications

References 32 publications

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB

Cortical excitatory neurons become protected from cell division during neurogenesis in an Rb family-dependent manner

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