B-myb and C-myb play required roles in neuronal apoptosis evoked by nerve growth factor deprivation and DNA damage

Department of Pathology, Center for Neurobiology and Behavior and Taub Center for Alzheimer's Disease Research, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2004; 24(40):8720-5. DOI: 10.1523/JNEUROSCI.1821-04.2004
Source: PubMed


Activation of cell cycle elements plays a required role in neuronal apoptosis associated with both development and neurodegenerative disorders. We demonstrated previously that neuron survival requires gene repression mediated by the cell cycle transcription factor E2F (E2 promoter binding factor) and that apoptotic stimuli lead to de-repression of E2F-regulated genes and consequent death. However, the downstream mediators of such death have been unclear. The transcription factors B- and C-myb are E2F-regulated genes that are induced in neurons by apoptotic stimuli. Here, we examine the role of B- and C-myb induction in neuron death. Antisense and siRNA constructs that effectively block the upregulation of B- and C-myb provide substantial protection against death of cultured neuronal PC12 cells, sympathetic neurons, and cortical neurons elicited by either NGF withdrawal or DNA damage. There is also significant protection from death induced by direct E2F-dependent gene de-repression. Our findings thus establish required roles for B- and C-myb in neuronal apoptosis.

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Available from: Subhas Biswas, Aug 14, 2014
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    • "We also observed elevated expression of E2F1 transcription factor at 24 h after TBI in CD1 + / + mice. E2F transcription factors induce apoptosis in neurons via activation of B-and C-myb genes (Liu et al., 2004), and induce expression of caspases-3, -9, and -8, and Apaf-1 (Nahle et al., 2002), as well asp53 and p73 activation (Greene et al., 2004). In addition, we demonstrate that CD1 expression remains elevated at least until 21 days post-injury. "
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    ABSTRACT: Cell cycle activation (CCA) is one of the principal secondary injury mechanisms following brain trauma, and it leads to neuronal cell death, microglial activation, and neurological dysfunction. Cyclin D1 (CD1) is a key modulator of CCA and is upregulated in neurons and microglia following traumatic brain injury (TBI). In this study we subjected CD1-wild-type (CD1(+/+)) and knockout (CD1(-/-)) mice to controlled cortical impact (CCI) injury to evaluate the role of CD1 in post-traumatic neurodegeneration and neuroinflammation. As early as 24 h post-injury, CD1(+/+) mice showed markers of CCA in the injured hemisphere, including increased CD1, E2F1, and proliferating cell nuclear antigen (PCNA), as well as increased Fluoro-Jade B staining, indicating neuronal degeneration. Progressive neuronal loss in the hippocampus was observed through 21 days post-injury in these mice, which correlated with a decline in cognitive function. Microglial activation in the injured hemisphere peaked at 7 days post-injury, with sustained increases at 21 days. In contrast, CD1(-/-) mice showed reduced CCA and neurodegeneration at 24 h, as well as improved cognitive function, attenuated hippocampal neuronal cell loss, decreased lesion volume, and cortical microglial activation at 21 days post-injury. These findings indicate that CD1-dependent CCA plays a significant role in the neuroinflammation, progressive neurodegeneration, and related neurological dysfunction resulting from TBI. Our results further substantiate the proposed role of CCA in post-traumatic secondary injury, and suggest that inhibition of CD1 may be a key therapeutic target for TBI.
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    • "We and others showed that Cdk4 regulates the activity of Rb by phosphorylation and its subsequent inactivation, and so releasing E2F transcription factors from inactivity (Giovanni et al., 2000; Park et al., 2000; Gendron et al., 2001). E2F activation in turn induces the upregulation of proapoptotic genes, such as B-and C-myb (Liu et al., 2004; Biswas et al., 2005; Greene et al., 2007). What is the link between cell cycle activation and Cited2? "
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    • "In mammals, the apoptotic loss of postmitotic neurons following the loss of trophic support from nerve growth factor (NGF) requires the derepression of multiple transcriptional pathways. These include the FoxO pathway , the c-Jun and c-Jun N-terminal kinase pathway ( JNK), and the cell cycle pathway, which involves phosphorylation of retinoblastoma (Rb) proteins as well as the derepression of Myb proteins (Brunet et al. 2001; Liu et al. 2004). All three of these pathways converge on Bim, a pro-apoptotic protein that is activated in response to NGF deprivation. "
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