How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

Hinkal, George; Donehower, Lawrence A.

doi:10.1016/j.mad.2008.02.005

Cited by 35 publications

(25 citation statements)

References 99 publications

(108 reference statements)

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“…IGF-I signaling impairment by oxidative stress has been recently confirmed by others in neurons (10,11) and others cell types (12). However, a substantial body of evidence in vertebrates and invertebrates also indicates that IGF-I signaling may reduce cell defenses to oxidative stress (13)(14)(15)) that, in turn, would affect neuron survival. These results question the neuroprotective role of IGF-I in response to brain oxidative insults.…”

Section: Igf-imentioning

confidence: 85%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/ FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H 2 O 2 ), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H 2 O 2 -exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury. IGF-I2 is a pleiotropic growth factor with important prosurvival effects in neurons (1). One of the main downstream targets of IGF-I is the Ser/Thr kinase AKT (2), which mediates cell survival and proliferation (3). Upon its activation, the IGF-I receptor recruits and phosphorylates IRS docking proteins (4), which allows translocation of phosphatidylinositol 3-kinase (PI3K) to the plasma membrane where it catalyzes the formation of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (5). AKT is recruited to the membrane by interaction with these messengers so that it can be fully activated by PDK1 and mTORC2 kinases (3,6). This pathway is switched off (to prevent uncontrolled proliferation) through activation of the lipid and protein phosphatase PTEN, which catalyzes PIP 3 dephosphorylation (4).Cell metabolism generates potentially harmful reactive oxygen species (ROS), which at moderate levels can act as second messengers (7). However, chronic and/or abrupt increases of ROS (uncontainable by detoxification through cellular defenses) generates oxidative stress, a pathological cellular condition that can interfere with redox-sensitive signaling pathways (7). Neurons are particularly vulnerable to oxidative stress because of their low ROS detoxifying capacity (8).We previously described that oxidative stress interferes with the IGF-I/PI3K/AKT pathway by redox activation of p38 kinase to induce neuronal death (9). IGF-I signaling impairment by oxidative stress ha...

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Section: Igf-imentioning

confidence: 85%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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“…These results are in accordance with a previous study where IGF-I expression is caused by oxidative stress, but is decreased by antioxidant agents [34]. In addittion, GH might regulate different signalling pathways [35].…”

Section: Discussionsupporting

confidence: 93%

Growth Hormone Prevents the Memory Deficit Caused by Oxidative Stress in Early Neurodegenerative Stage in Rats

Borgornio-Pérez¹,

Zentella‐Dehesa²,

Sandoval-Montiel³

et al. 2012

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Oxidative stress has been involved in neurodegenerative diseases. The growth hormone (GH) counteracts the levels of reactive oxygen species. Previously, we showed that the prolonged exposure to ozone causes oxidative stress in the hippocampus and memory deficits. In this work, we analyzed the effects of the growth hormone on the memory deficit generated by ozone exposure, growth hormone effects on the Insulin-like growth factor I (IGF-I), and the serinethreonine protein kinase (Akt) activation in the dentate gyrus. Our results show that GH prevents memory deficits in early stages of the neurodegenerative process.

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“…Enhanced production of thrombospondin 1 could be a compensatory mechanism for controlling the immune response and protecting tissues from excessive damage (44). In contrast, the role of IGF-1 may be related to the cytoprotection processes or metabolism in this tissue rather than regeneration (45). In summary, we demonstrated the engraftment of human CD133 þ BMDSCs around endometrial vessels of the traumatized endometrium of an immunodeficient AS mice model.…”

Section: Discussionmentioning

confidence: 75%

Human CD133+ bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome

Cervelló

Gil-Sanchís

Santamaría

et al. 2015

Fertility and Sterility

138

114

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How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

Cited by 35 publications

References 99 publications

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Growth Hormone Prevents the Memory Deficit Caused by Oxidative Stress in Early Neurodegenerative Stage in Rats

Human CD133+ bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome

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