ATM and ATR: Sensing DNA damage

Yang, Jun; Xu, Zhengping; Huang, Yun; Hamrick, Hope E.; Duerksen-Hughes, Penelope J.; Yu, Yingnian

doi:10.3748/wjg.v10.i2.155

Cited by 119 publications

(108 citation statements)

References 92 publications

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“…The cellular event involving active p53 is to stimulate the apoptotic infrastructure by increasing the expression of apoptotic protease-activating factor 1 (APAF-1), a crucial component of the apoptosome (Kinzler and Vogelstein, 1997;Levine, 1997). Functional proteins downstream from the p53 interactive signaling pathways, such as ataxia telangiectasia mutated (ATM) and homolog of ATM (ATR), are central to the DNA damage response (Zhou and Elledge, 2000;Goodarzi et al, 2003;Dodson et al, 2004;Irarrazabal et al, 2004;Kastan, 2004;Yang et al, 2004). Further downstream targets (substrates) of ATM/ATR include the checkpoint protein kinases Chk1 and Chk2 (Ma et al, 1998;Matsuoka et al, 1998;Sanchez et al, 1999;Tominaga et al, 1999).…”

Section: Role Of P53 In Uv Irradiation-induced Dna Damagementioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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Section: Role Of P53 In Uv Irradiation-induced Dna Damagementioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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“…DSB repair is defective in ATM-deficient Y. Zhao and others cells (Yang et al 2004). We thus assumed that the rate of DSB repair (Module 1) is proportional to the activity of phosphorylated ATM, and to the amount of DSBs.…”

Section: Modulementioning

confidence: 99%

Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

2011

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Rory B. Conolly ᮀ Hamner Institutes for Health Sciences, USA and US EPA ᮀ The shape of dose response of ionizing radiation (IR) induced cancer at low dose region, either linear non-threshold or J-shaped, has been a debate for a long time. This dose response relationship can be influenced by built-in capabilities of cells that minimize the fixation of IR-mediated DNA damage as pro-carcinogenic mutations. Key capabilities include sensing of damage, activation of cell cycle checkpoint arrests that provide time needed for repair of the damage as well as apoptosis. Here we describe computational modeling of the signaling pathways that link sensing of DNA damage and checkpoint arrest activation/apoptosis to investigate how these molecular-level interactions influence the dose response relationship for IR induced cancer. The model provides qualitatively accurate descriptions of the IR-mediated activation of cell cycle checkpoints and the apoptotic pathway, and of time-course activities and dose response of relevant regulatory proteins (e.g. p53 and p21). Linking to a two-stage clonal growth cancer model, the model described here successfully captured a monotonically increasing to a J-shaped dose response curve and identified one potential mechanism leading to the J-shape: the cell cycle checkpoint arrest time saturates with the increase of the dose.

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“…In addition to the positive regulation by cyclins/CDKs, the cell cycle is also controlled by negative regulatory proteins, such as CDK inhibitors, which mainly include two families: the INK4 and Cip/Kip families [1] . Additionally, cell cycle regulation is monitored by many checkpoints, such as the ATM/ATR pathway [2] . As summarized above, proper progression through the cell cycle is strictly monitored by various positive and negative surveillance factors.…”

Section: Introductionmentioning

confidence: 99%

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

Liang

2011

Acta Pharmacol Sin

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The cell cycle, which is precisely controlled by a number of regulators, including cyclins and cyclin-dependent kinases (CDKs), is crucial for the life cycle of mammals. Cell cycle dysregulation is implicated in many diseases, including cancer. Recently, compelling evidence has been found that microRNAs play important roles in the regulation of cell cycle progression by modulating the expression of cyclins, CDKs and other cell cycle regulators. Herein, the recent findings on the regulation of the cell cycle by microRNAs are summarized, and the potential implications of miRNAs in anti-cancer therapies are discussed.

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ATM and ATR: Sensing DNA damage

Cited by 119 publications

References 92 publications

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

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