Loss of dE2F Compromises Mitochondrial Function

Ambrus, Aaron M.; Islam, Abul B.M.M.K.; Holmes, Katherine B.; Moon, Nam Sung; López‐Bigas, Núria; Benevolenskaya, Elizaveta V.; Frolov, Maxim V.

doi:10.1016/j.devcel.2013.10.002

Cited by 30 publications

(35 citation statements)

References 45 publications

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“…Indeed, proteomic studies show that changes in mitochondrial function are a major feature of RB1 mutant mouse tissues (Nicolay et al 2015). While the mechanistic basis for these metabolic changes has not been fully elucidated, these results are consistent with reports showing that E2F and RB proteins bind directly to promoters of genes encoding important regulators of metabolic flux, oxidative phosphorylation, and mitochondrial function (Cam et al 2004;Hsieh et al 2008;Chicas et al 2010;Blanchet et al 2011;Ambrus et al 2013). Indeed, in Drosophila, E2F1 is needed for full activation of mitochondrial and muscle-specific genes during myogenic differentiation, and the presence of E2F in adult skeletal muscles is essential for animal viability (Zappia and Frolov 2016).…”

Section: The Cellular Consequences Of Rb Inactivationsupporting

confidence: 80%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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Section: The Cellular Consequences Of Rb Inactivationsupporting

confidence: 80%

RB1: a prototype tumor suppressor and an enigma

2016

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“…Two lines of experiments support this idea (11). Firstly, immunofluorescence and electron microscopy of dDP mutants revealed a highly fragmented and reduced mitochondrial network with mitochondria appearing to be more globular and swollen.…”

Section: E2f Regulates Mitochondrial Function In Drosophilamentioning

confidence: 91%

“…As dE2f1 directly regulates apoptotic genes, the simplest explanation is that the loss of E2F control prevents the induction of apoptotic genes in irradiated cells. This turned out to be not the case since gene expression microarrays revealed that the DNA damage-induced apoptotic transcriptional program is properly activated in the irradiated dDP mutants (11). Furthermore many of the apoptotic genes were expressed at a higher level in dDP mutants than in control animals prior to irradiation and induced to an even greater level following irradiation.…”

Section: E2f Regulates Mitochondrial Function In Drosophilamentioning

confidence: 99%

Emerging Links between E2F Control and Mitochondrial Function

Benevolenskaya

Frolov

2015

Cancer Research

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The family of E2F transcription factors is the key downstream target of the Retinoblastoma tumor suppressor protein (pRB), which is frequently inactivated in human cancer. E2F is best known for its role in cell cycle regulation and triggering apoptosis. However, E2F binds to thousands of genes and, thus, could directly influence a number of biological processes. Given the plethora of potential E2F targets, the major challenge in the field is to identify specific processes in which E2F plays a functional role and the contexts in which a particular subset of E2F targets dictates a biological outcome. Recent studies implicated E2F in regulation of expression of mitochondria-associated genes. The loss of such regulation results in severe mitochondrial defects. The consequences become evident during irradiation-induced apoptosis, where E2F-deficient cells are insensitive to cell death despite induction of canonical apoptotic genes. Thus, this novel function of E2F may have a major impact on cell viability, and it is independent of induction of apoptotic genes. Here, we discuss the implications of these findings in cancer biology.

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“…Interestingly a role of the Rbf1 and Drosophila E2F (dE2F) pathway in the regulation of mitochondrial function has been reported (Ambrus et al, 2013). Indeed Rbf1 and dE2F control the expression of genes encoding mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 99%

The Drosophila retinoblastoma protein, Rbf1, induces a debcl and drp1-dependent mitochondrial apoptosis.

Clavier

Ruby

Rincheval-Arnold

et al. 2015

Journal of Cell Science

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In accordance with its tumor suppressor role, the retinoblastoma protein pRb can ensure pro-apoptotic functions. Rbf1, the Drosophila homolog of Rb, also displays a pro-apoptotic activity in proliferative cells. We have previously shown that the Rbf1 pro-apoptotic activity depends on its ability to decrease the level of anti-apoptotic proteins such as the Bcl-2 family protein Buffy. Buffy often acts in an opposite manner to Debcl, the other Drosophila Bcl-2-family protein. Both proteins can localize at the mitochondrion, but the way they control apoptosis still remains unclear. Here, we demonstrate that Debcl and the pro-fission gene Drp1 are necessary downstream of Buffy to trigger a mitochondrial fragmentation during Rbf1-induced apoptosis. Interestingly, Rbf1-induced apoptosis leads to a Debcl-and Drp1-dependent reactive oxygen species production, which in turn activates the Jun Kinase pathway to trigger cell death. Moreover, we show that Debcl and Drp1 can interact and that Buffy inhibits this interaction. Notably, Debcl modulates Drp1 mitochondrial localization during apoptosis. These results provide a mechanism by which Drosophila Bcl-2 family proteins can control apoptosis, and shed light on a link between Rbf1 and mitochondrial dynamics in vivo.

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Loss of dE2F Compromises Mitochondrial Function

Cited by 30 publications

References 45 publications

RB1: a prototype tumor suppressor and an enigma

RB1: a prototype tumor suppressor and an enigma

Emerging Links between E2F Control and Mitochondrial Function

The Drosophila retinoblastoma protein, Rbf1, induces a debcl and drp1-dependent mitochondrial apoptosis.

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