Decreased brain infarct following focal ischemia in mice lacking the transcription factor E2F1

Jp, MacManus; Cj, Koch; Jian, Ming; Walker, Teena; Zurakowski, Bogdan

doi:10.1097/00001756-199909090-00004

Cited by 57 publications

(48 citation statements)

References 4 publications

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“…Because E2F-1 is known to regulate its own transcription, this result is consistent with the notion of deregulated activation of E2F-1 complexes during death induced by low K ϩ ; a concept suggested by previous reports demonstrating both Rb phosphorylation and loss in this same death paradigm (17). Our findings of significant neuroprotection as a result of E2F-1 deficiency are also consistent with the in vivo observations of others showing that E2F-1 deficiency is partially protective against death induced by Rb deficiency (46) and ischemia (59). In addition, we have also recently shown that E2F-1 deficiency is protective against ␤-amyloid toxicity (60).…”

Section: E2f-1 Expression Evokes Caspase Activation and Death In Asupporting

confidence: 93%

Induction and Modulation of Cerebellar Granule Neuron Death by E2F-1

O’Hare

Hou²,

Morris³

et al. 2000

Journal of Biological Chemistry

141

108

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Growing evidence suggests that certain cell cycle regulators also mediate neuronal death. Of relevance, cyclin D1-associated kinase activity is increased and the retinoblastoma protein (Rb), a substrate of the cyclin D1-Cdk4/6 complex, is phosphorylated during K ؉ deprivation-evoked death of cerebellar granule neurons (CGNs). Cyclin-dependent kinase (CDK) inhibitors block this death, suggesting a requirement for the cyclin D1/ Cdk4/6-Rb pathway. However, the downstream target(s) of this pathway are not well defined. The transcription factor E2F-1 is regulated by Rb and is reported to evoke death in proliferating cells when overexpressed. Accordingly, we examined whether E2F-1 was sufficient to evoke death of CGNs and whether it was required for death evoked by low K ؉ . We show that adenovirus-mediated expression of E2F-1 in CGNs results in apoptotic death, which is independent of p53, dependent upon Bax, and associated with caspase 3-like activity. In addition, we demonstrate that levels of E2F-1 mRNA and protein increase during K ؉ deprivation-evoked death. The increase in E2F-1 protein is blocked by the CDK inhibitor flavopiridol. Finally, E2F-1-deficient neurons are modestly resistant to death induced by low K ؉ . These results indicate that E2F-1 expression is sufficient to promote neuronal apoptosis and that endogenous E2F-1 modulates the death of CGNs evoked by low K ؉ .

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Section: E2f-1 Expression Evokes Caspase Activation and Death In Asupporting

confidence: 93%

Induction and Modulation of Cerebellar Granule Neuron Death by E2F-1

O’Hare

Hou²,

Morris³

et al. 2000

Journal of Biological Chemistry

141

108

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“…In addition, E2F1 expression is sufficient to promote the death of proliferating cells (39). Finally, E2F1-deficient mice are resistant to the death of cultured cortical and cerebellar granule neurons evoked by ␤-amyloid toxicity and low extracellular K ϩ , respectively (12) (M. O'Hare and D.S.P., unpublished data), and to ischemic damage (40). However, in these cases, protection is transient and͞or incomplete, suggesting the participation of additional, complementary death pathways.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinases as a therapeutic target for stroke

Osuga

Wang

et al. 2000

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

262

221

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Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4͞cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.T he mechanism by which stroke-induced neuronal death occurs is complex and is likely dependent upon the severity and duration of ischemic insult and an elaborate interplay between ischemic death initiators such as excitotoxicity, oxidative stress, DNA damage, and inflammatory responses (1-3). Neurons that survive the acute ischemic injury undergo a delayed cell death that exhibits some characteristics of apoptosis (1-3). This delayed cell death is dependent upon selected death-signaling elements such as caspases, poly(ADP-ribose) polymerase, and p53 (4). The identification of signaling molecules that control delayed neuronal death has led to the hope that some of these death-signaling elements may serve as useful therapeutic targets for the reduction of neuropathology and behavioral deficits associated with stroke injury. The mechanism by which stroke-evoked delayed death occurs, however, is not fully understood.The cell cycle is a highly coordinated process regulated by the appropriate and timely activation of cyclin-dependent kinases (CDKs) (5). Regulation of CDKs is complex and includes binding to their obligate cyclin partner, activating and inhibitory phosphorylation events, and endogenous inhibitors of CDK activity. Distinct CDKs regulate progressive phases of the cell cycle. Generally, it is thought that the Cdk4͞6͞cyclin D1 complex regulates the G 0 to G 1 , Cdk2͞cyclin E and Cdk3 control G 1 to S, and Cdk2͞cyclin A and Cdk1͞cyclin B control G 2 and M progressions. Although the downstream targets of CDKs are not fully characterized, one important substrate is the tumor suppresser retinoblastoma protein (pRb), which is phosphorylated by activated Cdk4͞6͞cyclin D complex (6). Once hyperphosphorylated, pRb is released from the transcription factor complex E2F͞DP, which then activates genes required for S phase transition (7-9).Paradoxically, increasing evidence suggests that CDKs may have functions beyond that of cell cycle regulation. Numerous reports indicate the requirement of CDK signals for death of cultured postmitotic neurons exposed to select death insults. For example, inappropriate cyclin B and cyclin D1 transcripts have been observed in neuronal P...

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“…In particular, it may function to promote the senescent state and may participate in neuronal apoptosis. E2F1 is known to have an important role in driving apoptosis in several cell types, including neurons (Giovanni et al, 2000;MacManus et al, 1999;Park et al, 2000). However, recent studies have shown that E2F2 can also exhibit pro-apoptotic activity (Dirks et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

E2F2 converts reversibly differentiated PC12 cells to an irreversible, neurotrophin-dependent state

Persengiev

Poulin

et al. 2001

Oncogene

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E2Fs play a central role in cell proliferation and growth arrest through their ability to regulate genes involved in cell cycle progression, arrest and apoptosis. Recent studies further indicate that this family of transcriptional regulators participate in cell fate/di erentiation events. They are thus likely to have a prominent role in controlling the terminal di erentiation process and its irreversibility. Here we have speci®cally examined the role of E2F2 in neuronal di erentiation using a gain-offunction approach. Endogenous E2F2 increased in PC12 cells in response to nerve growth factor (NGF) and was also expressed in cerebellar granule neurons undergoing terminal di erentiation. While PC12 cells normally undergo reversible dedi erentiation and cell cycle reentry upon NGF removal, forced expression of E2F2 inhibited these events and induced apoptosis. Thus, E2F2 converted PC12-derived neurons from a reversible to à terminally' di erentiated, NGF-dependent state, analogous to postmitotic sympathetic neurons. This contrasts with the e ects of E2F4, which enhances the di erentiation state of PC12 cells without a ecting cell cycle parameters or survival. These results indicate that E2F2 may have a unique role in maintaining the postmitotic state of terminally di erentiated neurons, and may participate in apoptosis in neurons attempting to reenter the cell cycle. It may also be potentially useful in promoting the terminally arrested/di erentiated state of tumor cells. Oncogene (2001) 20, 5124 ± 5131.

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Decreased brain infarct following focal ischemia in mice lacking the transcription factor E2F1

Cited by 57 publications

References 4 publications

Induction and Modulation of Cerebellar Granule Neuron Death by E2F-1

Induction and Modulation of Cerebellar Granule Neuron Death by E2F-1

Cyclin-dependent kinases as a therapeutic target for stroke

E2F2 converts reversibly differentiated PC12 cells to an irreversible, neurotrophin-dependent state

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