Metabolic Regulation of Hippocampal Neuroprogenitor Apoptosis After Irradiation

Abstract The tumor suppressor p53 is an important regulator of cell fate response after DNA damage. Cell fate response following metabolic stresses has also been linked to p53-dependent pathways. In this study, we asked if 5′-adenosine monophosphate-activated protein kinase (AMPK), the master sensor of cellular energy balance, played a role in p53-dependent apoptosis of neural progenitor cells (NPCs) in the hippocampus after irradiation. Adult mice with targeted disruption of p53 or prkaa2 (gene that encodes AMPKα) in the brain were used to determine the role of p53 and AMPK, respectively, in radiation-induced apoptosis of NPCs in the hippocampus. The p53-dependent apoptosis of NPCs was associated with an increase in phospho-AMPK expression in the dentate gyrus at 8 hours after irradiation. Activation of AMPK was seen in granule neurons and subgranular NPCs. Compared with wildtype mice, apoptosis of NPCs was significantly attenuated in AMPK deficient (nestinCre: prkaa2fl/fl) mice after irradiation. AMPK deficiency did not however alter p53 activation in NPCs after irradiation. We conclude that AMPK may regulate apoptosis of hippocampal NPCs after irradiation. These findings suggest that cellular metabolism may play a role in determining cell fate response such as apoptosis after DNA damage in NPCs.

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Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab014 ◽

2021 ◽

Vol 80 (5) ◽

pp. 467-475

Author(s):

Yu-Qing Li ◽

C Shun Wong

Keyword(s):

Cell Fate ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Neuronal Development ◽

Adenosine Monophosphate ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Wild Type ◽

Newborn Neuron ◽

Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

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ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. VOLUME 283 (2008) PAGES 6572-6583

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)71575-9 ◽

2008 ◽

Vol 283 (22) ◽

pp. 15512

Author(s):

Navjotsingh Pabla ◽

Shuang Huang ◽

Qing-Sheng Mi ◽

Rene Daniel ◽

Zheng Dong

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Damage Response ◽

P53 Activation ◽

Induced Apoptosis

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141 Combined Treatment With PPAR Gamma Ligands and Gamma Radiation Induced Apoptosis Through Up-regulation of ROS-induced DNA Damage Signals in Human Lung Cancer Cells

European Journal of Cancer ◽

10.1016/s0959-8049(12)70841-9 ◽

2012 ◽

Vol 48 ◽

pp. S34

Author(s):

S. Hong ◽

E. Han ◽

E. Lee ◽

J. Park

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Gamma Radiation ◽

Human Lung ◽

Combined Treatment ◽

Ppar Gamma ◽

Human Lung Cancer ◽

Human Lung Cancer Cells ◽

Radiation Induced ◽

Induced Apoptosis

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Geraniin down regulates gamma radiation-induced apoptosis by suppressing DNA damage

Food and Chemical Toxicology ◽

10.1016/j.fct.2013.03.022 ◽

2013 ◽

Vol 57 ◽

pp. 147-153 ◽

Cited By ~ 19

Author(s):

So Jin Bing ◽

Danbee Ha ◽

Min Ju Kim ◽

Eunjin Park ◽

Ginnae Ahn ◽

...

Keyword(s):

Dna Damage ◽

Gamma Radiation ◽

Radiation Induced ◽

Induced Apoptosis

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Abundance of cyclin B1 regulates γ-radiation–induced apoptosis

Blood ◽

10.1182/blood.v95.8.2645 ◽

2000 ◽

Vol 95 (8) ◽

pp. 2645-2650 ◽

Cited By ~ 114

Author(s):

Lisa A. Porter ◽

Gurmit Singh ◽

Jonathan M. Lee

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Mammalian Cells ◽

Hematopoietic Cells ◽

Cyclin B1 ◽

Regulatory Subunit ◽

Potent Inducer ◽

Γ Radiation ◽

Radiation Induced ◽

Induced Apoptosis

Abstract γ-Radiation is a potent inducer of apoptosis. There are multiple pathways regulating DNA damage-induced apoptosis, and we set out to identify novel mechanisms regulating γ-radiation–induced apoptosis in hematopoietic cells. In this report, we present data implicating the cyclin B1 protein as a regulator of apoptotic fate following DNA damage. Cyclin B1 is the regulatory subunit of the cdc2 serine/threonine kinase, and accumulation of cyclin B1 in late G2 phase of the cell cycle is a prerequisite for mitotic initiation in mammalian cells. We find that abundance of the cyclin B1 protein rapidly increases in several mouse and human hematopoietic cells (Ramos, DP16, HL60, thymocytes) undergoing γ-radiation–induced apoptosis. Cyclin B1 accumulation occurs in all phases of the cell cycle. Antisense inhibition of cyclin B1 accumulation decreases apoptosis, and ectopic cyclin B1 expression is sufficient to induce apoptosis. These observations are consistent with the idea that cyclin B1 is both necessary and sufficient for γ-radiation-induced apoptosis.

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Modification of radiation-induced apoptosis in radiation- or hyperthermia-adapted human lymphocytes

Biochemistry and Cell Biology ◽

10.1139/o94-064 ◽

1994 ◽

Vol 72 (11-12) ◽

pp. 475-482 ◽

Cited By ~ 18

Author(s):

S. P. Cregan ◽

D. R. Boreham ◽

P. R. Walker ◽

D. L. Brown ◽

R. E. J. Mitchel

Keyword(s):

Dna Damage ◽

Ionizing Radiation ◽

Adaptive Response ◽

Human Peripheral Blood ◽

Human Lymphocytes ◽

Fluorescence Analysis ◽

Terminal Deoxynucleotidyl Transferase ◽

Protective Mechanism ◽

Radiation Induced ◽

Induced Apoptosis

We have investigated the influence of the cellular adaptive response to ionizing radiation on radiation-induced apoptosis in human cells. The adaptive response is believed to be a protective mechanism that confers resistance to the detrimental effects of ionizing radiation and that can be induced by different agents, including hyperthermia and radiation. We have used fluorescence analysis of DNA unwinding (FADU) to assay the induction of apoptosis in human peripheral blood lymphocytes by ionizing radiation. Using the FADU assay, we have observed the initial radiation-induced DNA damage, its subsequent disappearance due to enzymatic repair, and its time- and dose-dependent reappearance. We believe this reappearance of DNA damage to be indicative of the DNA fragmentation event associated with apoptosis. This interpretation has been supported at the individual cell level using an in situ terminal deoxynucleotidyl transferase (TDT) assay (Apoptag, Oncor Inc.), which detects the 3′-hydroxyl ends of fragmented DNA, and by fluorescence analysis of nuclear morphology in Hoechst 33258 stained cells. Pretreatment of cells with low-dose γ-radiation (0.1 Gy) or mild hyperthermia (40 °C for 30 min) altered the extent of radiation-induced (3 Gy) apoptosis. Both pretreatments sensitized lymphocytes to become apoptotic after the 3-Gy radiation exposure. This sensitization may represent an adaptive response mechanism that reduces the risk that genetically damaged cells will proliferate. The ability to modify the probability of radiation-induced apoptosis may lower the cancer risk from a radiation exposure.Key words: apoptosis, adaptive response, ionizing radiation, hyperthermia.

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α-Melanocyte-stimulating Hormone Protects from Ultraviolet Radiation-induced Apoptosis and DNA Damage

Journal of Biological Chemistry ◽

10.1074/jbc.m406334200 ◽

2004 ◽

Vol 280 (7) ◽

pp. 5795-5802 ◽

Cited By ~ 163

Author(s):

Markus Böhm ◽

Ilka Wolff ◽

Thomas E. Scholzen ◽

Samantha J. Robinson ◽

Eugene Healy ◽

...

Keyword(s):

Dna Damage ◽

Ultraviolet Radiation ◽

Melanocyte Stimulating Hormone ◽

Radiation Induced ◽

Induced Apoptosis ◽

Stimulating Hormone

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The YeastTEL1Gene Partially Substitutes for HumanATMin Suppressing Hyperrecombination, Radiation-Induced Apoptosis and Telomere Shortening in A-T Cells

Molecular Biology of the Cell ◽

10.1091/mbc.11.8.2605 ◽

2000 ◽

Vol 11 (8) ◽

pp. 2605-2616 ◽

Cited By ~ 22

Author(s):

Eberhard Fritz ◽

Anna A. Friedl ◽

Ralf M. Zwacka ◽

Friederike Eckardt-Schupp ◽

M. Stephen Meyn

Keyword(s):

T Cells ◽

Clinical Phenotype ◽

Telomere Shortening ◽

Biochemical Pathways ◽

Radiation Induced ◽

P53 Activation ◽

Atm Gene ◽

Homozygous Mutations ◽

Atm Protein ◽

Induced Apoptosis

Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.

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