A novel conditional Akt ‘survival switch’ reversibly protects cells from apoptosis

Li, B; Desai, SA; MacCorkle-Chosnek, RA; Fan, Lir‐Wan; Spencer, D M

doi:10.1038/sj.gt.3301641

Cited by 46 publications

(33 citation statements)

References 71 publications

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“…It has been well known that PI3K triggers cytoprotective events in response to diverse stimuli (31)(32)(33). Interestingly, however, in this study we found that PI3K is critically required for the radiation-induced apoptotic cell death.…”

Section: Discussioncontrasting

confidence: 47%

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Kim

Choi

Park

et al. 2008

Molecular Cancer Research

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Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.

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Section: Discussioncontrasting

confidence: 47%

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Kim

Choi

Park

et al. 2008

Molecular Cancer Research

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“…The activation of Akt plays a critical role in fundamental cellular functions such as cell proliferation and survival by phosphorylation of a variety of substrates (36)(37)(38). Constitutively active Akt results in augmented resistance against apoptotic cellular insults, such as growth factor deprivation, UV irradiation, or loss of matrix attachment (39). Akt activation is found in many types of human tumors including breast cancer, lung cancer, melanoma, and leukemia (40,41).…”

Section: Discussionmentioning

confidence: 99%

PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer

Jung

Kang²,

Kim³

et al. 2010

Int J Mol Med

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Abstract.The sensitivity or resistance of cancer cells and normal tissues to ionizing radiation plays an important role in the clinical setting of lung cancer treatment. However, to date the exact molecular mechanisms of intrinsic radiosensitivity have not been well explained. In this study, we compared the radiosensitivity or radioresistance in two non-small cell lung cancers (NSCLCs), H460 and A549, and investigated the signaling pathways that confer radioresistance. H460 cells showed a significant G 2 /M arrest after 12 h of irradiation (5 Gy), reaching 60% of G 2 /M phase arrest. A549 cells also showed a significant G 2 /M arrest after 12 h of exposure; however, this arrest completely disappeared after 24 h of exposure. A549 has higher methylated CpG sites in PTEN, which is correlated with tumor radioresistance in some cancer cells, than H460 cells, and the average of the extent of the methylation was ~4.3 times higher in A549 cells than in H460 cells. As a result, PTEN expression was lower in A549 than in H460. Conducting Western blot analysis, we found that PTEN acted as a negative regulator for pAkt, and the pAkt acted as a negative regulator for p53 expression. According to the above results, we concluded that the radiosensitivity shown in H460 cells may be due to the higher expression of PTEN through p53 signaling pathway.

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“…Although constitutively active Akt provides a significant survival advantage in animal models of sepsis, chronic expression of constitutively active Akt resulted in lymphomas in 60% of mice (12). Conditional activation of Akt has been demonstrated using both a tetracycline-inducible model system (13) and chemical activation using rapalog-induced membrane association (14). These methods have resulted in remarkable phenotypes: rapid, reversible cardiac hypertrophy (13) and resistance to multiple apoptotic stimuli (14).…”

mentioning

confidence: 99%

“…Conditional activation of Akt has been demonstrated using both a tetracycline-inducible model system (13) and chemical activation using rapalog-induced membrane association (14). These methods have resulted in remarkable phenotypes: rapid, reversible cardiac hypertrophy (13) and resistance to multiple apoptotic stimuli (14). While these systems are attractive, they require transgenic manipulations of the host and do not represent viable therapeutic strategies.…”

mentioning

confidence: 99%

Peptide‐mediated activation of Akt and extracellular regulated kinase signaling prevents lymphocyte apoptosis

McDunn¹,

Muenzer²,

Rachdi³

et al. 2007

FASEB j.

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Lymphocyte apoptosis is a hallmark of sepsis and contributes to disease mortality. In other acute injuries, such as myocardial and cerebral ischemia/reperfusion, apoptosis plays a significant role in disease-associated morbidity and mortality. We previously showed that constitutive activation of the potent antiapoptotic Akt/protein kinase B signaling pathway in lymphocytes both reduces sepsisinduced lymphocyte apoptosis and confers a significant survival advantage compared to wild-type littermates. Here, we demonstrate a therapeutic approach to acutely augment Akt activity in a wildtype animal. A cell-permeable peptide conjugated to the Akt-binding domain of the endogenous Akt coactivator, Tcl-1, prolongs Akt activity, activates extracellular regulated kinase (ERK) signaling and protects lymphocytes from numerous apoptotic stimuli both in vitro and in vivo. Molecular approaches to activate the antiapoptotic Akt and ERK signaling pathways may provide a novel tool to study these signaling pathways, as well as a new antiapoptotic strategy for the treatment of sepsis and other acute injuries.SEPSIS AFFECTS 750,000 PATIENTS in the United States annually with nearly 30% mortality (1). Despite advances in patient care, the number of cases continues to rise. One difficulty in treating sepsis is that the pathogen causing infection is frequently not identified. As a result, it is difficult to know whether a therapeutic regimen is appropriate, and thus empiric antibiotics are often given. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAlthough a number of approaches are being explored to better diagnose and stage patients with sepsis, none have reached maturity (2).An alternative to current, pathogen-targeted therapies is the development of therapeutic approaches that ameliorate the pathological aspects of the host response (3-6). A common histopathological finding in septic patients at autopsy and in animal models of sepsis is the profound loss of lymphocytes by apoptosis (7). Prevention of sepsis-induced lymphocyte apoptosis confers a significant survival advantage in animal models of disease (8,9). One transgenic mouse that has a significant survival advantage in models of sepsis overexpresses Akt in a T-lymphocyte-restricted manner (10). These mice express a variant of Akt that has an N-terminal myristoylation sequence that results in Akt being constitutively active. Akt is a serine-threonine protein kinase that is activated in response to cell-stimulatory signals, such as growth factors, cytokines, and T cell activation. Akt inactivates a number of proapoptotic molecules, including GSK-3β, Bad, and forkhead transcription factors. As a result, activation of Akt renders a cell transiently refractory to apoptotic stimuli.Endogenous Akt is activated in response to many cell stimuli, however, these stimuli initiate a number of other cellular processes that are independent of Akt. The recent failure of anti-CD28 in phase I safety trials highlights the danger of activating several cell sign...

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A novel conditional Akt ‘survival switch’ reversibly protects cells from apoptosis

Cited by 46 publications

References 71 publications

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

PTEN/pAkt/p53 signaling pathway correlates with the radioresponse of non-small cell lung cancer

Peptide‐mediated activation of Akt and extracellular regulated kinase signaling prevents lymphocyte apoptosis

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