Role of DNA‐dependent protein kinase in neuronal survival

Chechlacz, Magdalena; Vemuri, Mohan C.; Naegele, Janice R.

doi:10.1046/j.1471-4159.2001.00380.x

Cited by 54 publications

(40 citation statements)

References 79 publications

(88 reference statements)

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“…This is despite the fact that DNA-PK was cleaved by the caspases during apoptosis in these cells. A DNA-PK deficiency in the cultured neurons caused an accumulation of DNA damage and increased susceptibility to caspase-independent forms of apoptosis (74). Therefore, the exact mechanism by which the selective reduction of Ku occurs during the apoptosis is unclear.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Induces Nuclear Loss of DNA Repair Proteins Ku70 and Ku80 and Apoptosis in Pancreatic Acinar AR42J Cells

Song

Lim

Kim

et al. 2003

Journal of Biological Chemistry

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Cell death linked to oxidative DNA damage has been implicated in acute pancreatitis. The severe DNA damage, which is beyond the capacity of the DNA repair proteins, triggers apoptosis. It has been hypothesized that oxidative stress may induce a decrease in the Ku70 and Ku80 levels and apoptosis in pancreatic acinar cells. In this study, it was found that oxidative stress caused by glucose oxidase (

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress Induces Nuclear Loss of DNA Repair Proteins Ku70 and Ku80 and Apoptosis in Pancreatic Acinar AR42J Cells

Song

Lim

Kim

et al. 2003

Journal of Biological Chemistry

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“…Interestingly, cells from Ku70 knockout mice are hypersensitive to agents that induce apoptosis in the absence of DNA damage, such as staurosporine. 43 This suggests that Ku70 plays a role in suppressing apoptosis that is independent of its role in DNA repair. 42 Based on these findings, nuclear Ku70 is therefore considered to be mainly responsible for repair of DNA damage, whereas the cytosolic pool of Ku70 may be primarily a regulator of Bax activation.…”

Section: Bax Activation In Apoptosismentioning

confidence: 99%

A Jekyll and Hyde Role of Cyclin E in the Genotoxic Stress Response: Switching from Cell Cycle Control to Apoptosis Regulation

Mazumder¹,

Plesca²

2007

Cell Cycle

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Cyclin E protein levels and associated kinase activity rise in late G 1 phase, reach a peak at the G 1 /S transition, and quickly decline during S phase. The cyclin E/Cdk2 complex has a well-established function in regulating two fundamental biological processes: cell cycle progression and DNA replication. However, cyclin E expression is deregulated in a wide range of tumors. Our recent reports have uncovered a critical role for cyclin E, independent of Cdk2, in the cell death of hematopoietic tumor cells exposed to genotoxic stress. An 18-kD C-terminal fragment of cyclin E, p18-cyclin E, which is generated by caspase-mediated cleavage in hematopoietic cells during genotoxic stressinduced apoptosis has a critical role in the amplification of the intrinsic apoptotic pathway. By interacting with Ku70, p18-cyclin E liberates Bax, which participates in the amplification of apoptosis by sustaining a positive feedback loop targeting mitochondria. This process is independent of p53 function and new RNA or protein synthesis. Therefore, cyclin E emerges as an arbiter of the genotoxic stress response by regulating a finite physiological balance between cell proliferation and death in hematopoietic cells.Keywords cyclin E; Cdk2; Ku70; Bax; caspase; apoptosis; cell cycle; genotoxic stress CDK2 Dependent Roles of Cyclin ECyclins regulate cell cycle progression by binding to their catalytic interacting partners, cyclin dependent kinases (Cdks). The activity of Cdk's is positively controlled by cyclins and negatively by binding to Cdk inhibitors (CKIs). 1,2 The transit between the G 1 and S phases of the cell cycle is primarily regulated by the cyclin E/Cdk2 complex. 3,4 Even though D-type cyclins are also involved in the G 1 /S transition, all phenotypic and developmental defects in mice caused by cyclin D1 deficiency can be rescued by cyclin E knock-in at the cyclin D1 locus, indicating that the function of cyclin D1 may be replaced by cyclin E. 5 Cyclin E1, referred to here as cyclin E, is the best known E-type cyclin and has 395 amino acids and a molecular weight of 50 kDa. 6,7 In normal cells, many gene products required for S-phase progression are under the control of the E2F family of transcription factors, which become free upon phosphorylation of the retinoblastoma protein (Rb) by cyclin E/Cdk2. Constitutive or ectopic expression of cyclin E can accelerate G 1 progression 4 and chromosome instability, 8,9 presumably because of inappropriate S-phase entry/progression. 10 The cyclin E/Cdk2 complex plays an important role in the initiation of DNA replication. 4,11 In Xenopus, there is strong evidence implicating cyclin E/Cdk2 in the initiation of DNA replication and in centrosome duplication. 12 A recent report in mammals indicates that cyclin E also plays a kinase-independent function in DNA replication by facilitating minichromosome maintenance (MCM) loading through physical interaction with CDT1 and MCM. 13The expression of cyclin E oscillates during cell cycle progression due to tight regulation at transcript...

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“…The mice lack a functional DNA repair mechanism for VDJ gene segment recombination (42). Neurons in adult mice are often more susceptible to apoptotic death (43,44), and tissue recovery after traumatic and inflammatory insults can be delayed (45,46). Despite these limitations, the model permitted the study of key features of HIVE and HAD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Neuroregulatory Events Follow Adaptive Immune-Mediated Elimination of HIV-1-Infected Macrophages: Studies in a Murine Model of Viral Encephalitis

Poluektova

Gorantla

Faraci

et al. 2004

The Journal of Immunology

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HIV-1-specific cellular immunity serves to eliminate infected cells and disease. However, how this process specifically affects the CNS is poorly understood. To mirror the regulatory events that occur in human brain after HIV-1 infection, a murine model of viral encephalitis was used to study relationships, over time, among lymphocyte-mediated infected cell elimination, innate immune responses, and neuropathology. Nonobese diabetic SCID mice were reconstituted with human PBL and a focal encephalitis induced by intracranial injection of autologous HIV-1-infected, monocyte-derived macrophages (MDM). On days 7, 14, and 21 after MDM injection into the basal ganglia, the numbers of human lymphocytes and mouse monocytes, virus-infected MDM, glial (astrocyte and microglial) responses, cytokines, inducible NO (iNOS), neurotrophic factors, and neuronal Ags were determined in brain by immunohistochemistry, real-time PCR, and Western blot assays. Microglia activation, astrocytosis, proinflammatory cytokines, and iNOS expression accompanied the loss of neuronal Ags. This followed entry of human lymphocytes and mouse monocytes into the brain on days 7 and 14. Elimination of virus-infected human MDM, expression of IL-10, neurotropins, and a down-regulation of iNOS coincided with brain tissue restoration. Our results demonstrate that the degree of tissue damage and repair parallels the presence of infected macrophages and effectors of innate and adaptive immunity. This murine model of HIV-1 encephalitis can be useful in elucidating the role played by innate and adaptive immunity in disease progression and resolution.

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Role of DNA‐dependent protein kinase in neuronal survival

Cited by 54 publications

References 79 publications

Oxidative Stress Induces Nuclear Loss of DNA Repair Proteins Ku70 and Ku80 and Apoptosis in Pancreatic Acinar AR42J Cells

Oxidative Stress Induces Nuclear Loss of DNA Repair Proteins Ku70 and Ku80 and Apoptosis in Pancreatic Acinar AR42J Cells

A Jekyll and Hyde Role of Cyclin E in the Genotoxic Stress Response: Switching from Cell Cycle Control to Apoptosis Regulation

Neuroregulatory Events Follow Adaptive Immune-Mediated Elimination of HIV-1-Infected Macrophages: Studies in a Murine Model of Viral Encephalitis

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