Ablation of Akt2 Induces Autophagy through Cell Cycle Arrest, the Downregulation of p70S6K, and the Deregulation of Mitochondria in MDA-MB231 Cells

Santi, Stacey A.; Lee, Hoyun

doi:10.1371/journal.pone.0014614

Cited by 62 publications

(67 citation statements)

References 63 publications

(76 reference statements)

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“…In addition, AKT2-deficient mice on HFD have reduced mTORC1 activation and increased autophagy that correlates with reduced hypertrophy and improved cardiac function (158). Of note, knockdown of AKT2 in cancer cells specifically activates mitophagy and can cause cell death from excessive removal of mitochondria (133).…”

Section: Myocardial Autophagy In T2d Animal Modelsmentioning

confidence: 99%

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Kubli

Gustafsson

2015

Antioxidants & Redox Signaling

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Significance: Diabetes is strongly associated with increased incidence of heart disease and mortality due to development of diabetic cardiomyopathy. Even in the absence of cardiovascular disease, cardiomyopathy frequently arises in diabetic patients. Current treatment options for cardiomyopathy in diabetic patients are the same as for nondiabetic patients and do not address the causes underlying the loss of contractility. Recent Advances: Although there are numerous distinctions between Type 1 and Type 2 diabetes, recent evidence suggests that the two disease states converge on mitochondria as an epicenter for cardiomyocyte damage. Critical Issues: Accumulation of dysfunctional mitochondria contributes to cardiac tissue injury in both acute and chronic conditions. Removal of damaged mitochondria by macroautophagy, termed ''mitophagy,'' is critical for maintaining cardiomyocyte health and contractility both under normal conditions and during stress. However, very little is known about the involvement of mitophagy in the pathogenesis of diabetic cardiomyopathy. A growing interest in this topic has given rise to a wave of publications that aim at deciphering the status of autophagy and mitophagy in Type 1 and Type 2 diabetes. Future Directions: This review summarizes these recent studies with the goal of drawing conclusions about the activation or suppression of autophagy and mitophagy in the diabetic heart. A better understanding of how autophagy and mitophagy are affected in the diabetic myocardium is still needed, as well as whether they can be targeted therapeutically. Antioxid. Redox Signal. 22, 1527Signal. 22, -1544

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Section: Myocardial Autophagy In T2d Animal Modelsmentioning

confidence: 99%

Unbreak My Heart: Targeting Mitochondrial Autophagy in Diabetic Cardiomyopathy

Kubli

Gustafsson

2015

Antioxidants & Redox Signaling

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“…In a similar way, ablation of Akt was shown to downregulate CDK4 and CDK6 expression [53,54]. Thus, it seems that PGRN-dependent PI3K/Akt and ERK1/2 activation plays a critical role as mediator of cell survival by regulating the activity of the CDK4/6/pRb pathway.…”

Section: Discussionmentioning

confidence: 85%

Progranulin Deficiency Reduces CDK4/6/pRb Activation and Survival of Human Neuroblastoma SH-SY5Y Cells

et al. 2014

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Null mutations in GRN are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). However, the influence of progranulin (PGRN) deficiency in neurodegeneration is largely unknown. In neuroblastoma cells, silencing of GRN gene causes significantly reduced cell survival after serum withdrawal. The following observations suggest that alterations of the CDK4/6/retinoblastoma protein (pRb) pathway, secondary to changes in PI3K/Akt and ERK1/2 activation induced by PGRN deficiency, are involved in the control of serum deprivation-induced apoptosis: (i) inhibiting CDK4/6 levels or their associated kinase activity by sodium butyrate or PD332991 sensitized control SH-SY5Y cells to serum deprivation-induced apoptosis without affecting survival of PGRN-deficient cells; (ii) CDK4/6/pRb seems to be downstream of the PI3K/Akt and ERK1/2 signaling pathways since their specific inhibitors, LY294002 and PD98059, were able to decrease CDK6-associated kinase activity and induce death of control SH-SY5Y cells; (iii) PGRN-deficient cells show reduced stimulation of PI3K/Akt, ERK1/2, and CDK4/6 activities compared with control cells in the absence of serum; and (iv) supplementation of recombinant human PGRN was able to rescue survival of PGRN-deficient cells. These observations highlight the important role of PGRN-mediated stimulation of the PI3K/Akt-ERK1/2/CDK4/6/pRb pathway in determining the cell fate survival/death under serum deprivation.

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“…Our understanding of the distinct roles of Akt isoforms in tumor development is still limited, but several studies report isoform-specific functions of Akt kinases. The role of Akt2 is suggested to be more important than the other isoforms regarding cell cycle progression, cell proliferation (22) and metabolism (23). The molecular mechanisms that lead to the different functions of Akt isoforms are unclear.…”

Section: Discussionmentioning

confidence: 99%