ATM-dependent ERK signaling via AKT in response to DNA double-strand breaks

Khalil, Ashraf; Morgan, Rhiannon N.; Adams, Bret R.; Golding, Sarah E.; Dever, Seth M.; Rosenberg, Elizabeth; Povirk, Lawrence F.; Valerie, Kristoffer

doi:10.4161/cc.10.3.14713

Cited by 71 publications

(62 citation statements)

References 50 publications

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“…The induction of IL-8 signaling following CXCR1/CXCR2 interaction activates multiple signaling pathways and, as a consequence, triggers different effectors and downstream targets to promote angiogenic responses in ECs (29). PI3K is one of the principal effectors of IL-8, resulting in increased phosphorylation of its substrate serine/threonin kinase Akt (30), whose role in EC angiogenesis is well established (31). IL-8 signaling has also been shown to induce the activation of ERK1/2.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

Caccuri¹,

Giagulli²,

Bugatti³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

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Vascular diseases supported by aberrant angiogenesis have increased incidence in HIV-1-infected patients. Several data suggest that endothelium dysfunction relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. The HIV-1 matrix protein p17 is known to deregulate the biological activity of different immune cells. Recently, p17 was found to mimic IL-8 chemokine activity by binding to the IL-8 receptor CXCR1. Here we show that p17 binds with high affinity to CXCR2, a CXCR1-related receptor, and promotes the formation of capillary-like structures on human endothelial cells (ECs) by interacting with both CXCR1 and CXCR2 expressed on the EC surface. ERK signaling via Akt was defined as the pathway responsible for p17-induced tube formation. Ex vivo and in vivo experimental models confirmed the provasculogenic activity of p17, which was comparable to that induced by VEGF-A. The hypothesis of a major role for p17 in HIV-1-induced aberrant angiogenesis is enforced by the finding that p17 is detected, as a single protein, in blood vessels of HIV-1-patients and in particular in the nucleus of ECs. Localization of p17 in the nucleus of ECs was evidenced also in in vitro experiments, suggesting the internalization of exogenous p17 in ECs by mechanisms of receptormediated endocytosis. Recognizing p17 interaction with CXCR1 and CXCR2 as the key event in sustaining EC aberrant angiogenesis could help us to identify new treatment strategies in combating AIDSrelated vascular diseases. extracellular viral proteins | virokine | Akt-mediated ERK pathway | vasculogenic assays | surface plasmon resonance A ngiogenesis is a physiological process requiring growth of new blood vessels from preexisting vessels. This process involves coordinated endothelial cell (EC) proliferation, invasion, migration, and tube formation (1). When new vessels are required, proangiogenic factors are produced, whereas restoration of physiological conditions is achieved by producing inhibitors of angiogenesis and vessel stabilization factors. Breakdown of the tight regulated angiogenic balance leads to dysfunctional endothelium, abnormal angiogenesis, and vascular diseases.

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Section: Resultsmentioning

confidence: 99%

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

Caccuri¹,

Giagulli²,

Bugatti³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

106

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“…A very recent study suggested that DSB can influence ERK signaling via an ATM/AKT-dependent pathway, 48 and our data provide a mechanistic framework that helps to explain this phenomena. Furthermore, our finding that the MRE11 endonuclease activity is not required for DSB-induced pAKT-S473 suggests that this phosphorylation is not dependent on DSB resection.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 96%

MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks

Fraser¹,

Harding²,

Zhao³

et al. 2011

Cell Cycle

104

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“…The radiosensitivity of GBM cells can be affected by AKT and ERK signaling pathways through promoting the activation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) (28). ERK and AKT signaling pathways have positive effects on DSB repair in an ATM-dependent manner (29). It has been discovered that ATM indirectly induces AKT and ERK phosphorylation, and inhibiting the ATM kinase with an ATM-specific inhibitor was found to reduce the phosphorylation of AKT and ERK (30,31).…”

Section: Discussionmentioning

confidence: 99%

β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway

et al. 2015

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Abstract. Glioblastoma multiforme (GBM), a tumor associated with poor prognosis, is known to be resistant to radiotherapy and alkylating agents such as temozolomide (TMZ). β-elemene, a monomer found in Chinese traditional herbs extracted from Curcuma wenyujin, is currently being used as an antitumor drug for different types of tumors including GBM. In the present study, we investigated the roles of β-elemene in the radiosensitivity and chemosensitivity of GBM cells. Human GBM cell lines U87-MG, T98G, U251, LN229 and rat C6 cells were treated with β-elemene combined with radiation or TMZ. We used MTT and colony forming assays to evaluate the proliferation and survival of the cells, and the comet assay to observe DNA damage. Expression of proteins was analyzed by immunoblotting. In the present study, we found that β-elemene inhibited the proliferation and survival of different GBM cell lines when combined with radiotherapy or TMZ via inhibition of DNA damage repair. Treatment of GBM cells with β-elemene decreased the phosphorylation of ataxia telangiectasia mutated (ATM), AKT and ERK following radiotherapy or chemotherapy. These results revealed that β-elemene could significantly increase the radiosensitivity and chemosensitivity of GBM. β-elemene may be used as a potential drug in combination with the radiotherapy and chemotherapy of GBM.

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ATM-dependent ERK signaling via AKT in response to DNA double-strand breaks

Cited by 71 publications

References 50 publications

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks

β-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway

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