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MicroRNA‑34a induces apoptosis in PC12 cells by reducing B‑cell lymphoma 2 and sirtuin‑1 expression.

Lin Q, Mao Y, Song Y, Huang D - Mol Med Rep (2015)

Bottom Line: The effect of miR‑34a in PC12 cells has not yet been reported.It was demonstrated that induction of miR‑34a promotes apoptosis and senescence, inhibits proliferation, and leads to marked alterations in SIRT1, Bcl‑12 and acetyl (ac)‑p53 expression.These data indicate that miR‑34a may be important in neuropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China.

ABSTRACT
MicroRNA‑34a (miR‑34a) is a direct target of p53 and was reported to induce cell cycle arrest, apoptosis and senescence. Inhibition of the NAD‑dependent deacetylase sirtuin‑1 (SIRT1) by miR‑34a leads to an increase in acetylated p53, which promotes cell apoptosis. B‑cell lymphoma 2 (Bcl‑2) is also involved in apoptosis, and was originally characterized with respect to its role in controlling outer mitochondrial membrane integrity. The effect of miR‑34a in PC12 cells has not yet been reported. In the present study, it was hypothesized that Bcl‑2 and SIRT1 may be critical downstream targets of miR‑34a that participate in apoptosis induction. miR‑34a mimics and inhibitors were transfected into PC12 cells, and the apoptosis and proliferation rates were compared between groups. It was demonstrated that induction of miR‑34a promotes apoptosis and senescence, inhibits proliferation, and leads to marked alterations in SIRT1, Bcl‑12 and acetyl (ac)‑p53 expression. These data indicate that miR‑34a may be important in neuropathy.

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Proposed feedback loop and apoptosis mechanism involving miR-34a, p53, SIRT1 and Bcl-2. miR-34a, microRNA-34a; SIRT1, sirtuin 1; Bcl-2, B-cell lymphoma 2; cyto C, cytochrome c.
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f5-mmr-12-04-5709: Proposed feedback loop and apoptosis mechanism involving miR-34a, p53, SIRT1 and Bcl-2. miR-34a, microRNA-34a; SIRT1, sirtuin 1; Bcl-2, B-cell lymphoma 2; cyto C, cytochrome c.

Mentions: As demonstrated in the present study, transfection of PC12 cells with miR-34a mimics resulted in insignificant alterations in cell viability compared with the control group. Apoptosis analysis by flow cytometry revealed that the apoptosis rate of the miR-34a mimic group was significantly higher compared with the control group. Consistently, compared with the control group, the expression of Bcl-2 and SIRT1 in the miR-34a mimic group was decreased, while the ac-p53 was increased. Cell senescence is a form of stagnation of cell growth and, the results obtained using the SA-β-gal staining assay showed that the miR-34a mimic greatly increased the SA-β-gal activity, suggesting that the miR34a mimic could increase the senescence of PC12 cells. miR-34a binds to the 3′-UTR sequences of SIRT1 mRNA, immediately inhibiting the translation of SIRT1. The decrease in SIRT1 expression leads to an increase in the acetylation of p53, enhancing p53 transcriptional activity, through the positive feedback loop as shown in Fig. 5. As a highly-conserved NAD+ induced deacetylase enzyme, SIRT1 was first identified in yeast, where, through regulation of downstream targets, such as p53, Foxo and Ku79, it is involved in reducing oxidative stress and apoptosis, and regulating gene silencing and cell cycle progression (30–32). SIRT1 promotes the deacetylation of c-terminal lysine 382 of the p53 protein, regulating the transcriptional activity of p53 and inhibiting p53-induced apoptosis (33). It is also reported that p53 can inhibit autophagy by reducing expression of SestrinZ and Draln, and accelerating cellular senescence (34,35). Studies have revealed that the deposition of β-amyloid protein (Aβ) is a critical initiating factor in Alzheimer's disease, and Aβ is a direct contributor to the neurofibrillary tangles in the brain and results in the loss of neurons (36). In models of Alzheimer's disease, high expression of SIRT1 in rat brains was found to strengthen the catabolic pathway of the amyloid protein, and reduce Aβ deposition (37). The present study showed that transfection of miR-34a mimics can effectively reduce the expression of SIRT1 in PC12 cells, while transfection of miR-34a inhibitors can increase the expression of SIRT1. Therefore, it was demonstrated that miR-34a activates SIRT1, which, due to the roles of SIRT1 in Alzheimer's disease, indicates that miR-34a may aid in preventing and curing Alzheimer's disease.


MicroRNA‑34a induces apoptosis in PC12 cells by reducing B‑cell lymphoma 2 and sirtuin‑1 expression.

Lin Q, Mao Y, Song Y, Huang D - Mol Med Rep (2015)

Proposed feedback loop and apoptosis mechanism involving miR-34a, p53, SIRT1 and Bcl-2. miR-34a, microRNA-34a; SIRT1, sirtuin 1; Bcl-2, B-cell lymphoma 2; cyto C, cytochrome c.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581806&req=5

f5-mmr-12-04-5709: Proposed feedback loop and apoptosis mechanism involving miR-34a, p53, SIRT1 and Bcl-2. miR-34a, microRNA-34a; SIRT1, sirtuin 1; Bcl-2, B-cell lymphoma 2; cyto C, cytochrome c.
Mentions: As demonstrated in the present study, transfection of PC12 cells with miR-34a mimics resulted in insignificant alterations in cell viability compared with the control group. Apoptosis analysis by flow cytometry revealed that the apoptosis rate of the miR-34a mimic group was significantly higher compared with the control group. Consistently, compared with the control group, the expression of Bcl-2 and SIRT1 in the miR-34a mimic group was decreased, while the ac-p53 was increased. Cell senescence is a form of stagnation of cell growth and, the results obtained using the SA-β-gal staining assay showed that the miR-34a mimic greatly increased the SA-β-gal activity, suggesting that the miR34a mimic could increase the senescence of PC12 cells. miR-34a binds to the 3′-UTR sequences of SIRT1 mRNA, immediately inhibiting the translation of SIRT1. The decrease in SIRT1 expression leads to an increase in the acetylation of p53, enhancing p53 transcriptional activity, through the positive feedback loop as shown in Fig. 5. As a highly-conserved NAD+ induced deacetylase enzyme, SIRT1 was first identified in yeast, where, through regulation of downstream targets, such as p53, Foxo and Ku79, it is involved in reducing oxidative stress and apoptosis, and regulating gene silencing and cell cycle progression (30–32). SIRT1 promotes the deacetylation of c-terminal lysine 382 of the p53 protein, regulating the transcriptional activity of p53 and inhibiting p53-induced apoptosis (33). It is also reported that p53 can inhibit autophagy by reducing expression of SestrinZ and Draln, and accelerating cellular senescence (34,35). Studies have revealed that the deposition of β-amyloid protein (Aβ) is a critical initiating factor in Alzheimer's disease, and Aβ is a direct contributor to the neurofibrillary tangles in the brain and results in the loss of neurons (36). In models of Alzheimer's disease, high expression of SIRT1 in rat brains was found to strengthen the catabolic pathway of the amyloid protein, and reduce Aβ deposition (37). The present study showed that transfection of miR-34a mimics can effectively reduce the expression of SIRT1 in PC12 cells, while transfection of miR-34a inhibitors can increase the expression of SIRT1. Therefore, it was demonstrated that miR-34a activates SIRT1, which, due to the roles of SIRT1 in Alzheimer's disease, indicates that miR-34a may aid in preventing and curing Alzheimer's disease.

Bottom Line: The effect of miR‑34a in PC12 cells has not yet been reported.It was demonstrated that induction of miR‑34a promotes apoptosis and senescence, inhibits proliferation, and leads to marked alterations in SIRT1, Bcl‑12 and acetyl (ac)‑p53 expression.These data indicate that miR‑34a may be important in neuropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China.

ABSTRACT
MicroRNA‑34a (miR‑34a) is a direct target of p53 and was reported to induce cell cycle arrest, apoptosis and senescence. Inhibition of the NAD‑dependent deacetylase sirtuin‑1 (SIRT1) by miR‑34a leads to an increase in acetylated p53, which promotes cell apoptosis. B‑cell lymphoma 2 (Bcl‑2) is also involved in apoptosis, and was originally characterized with respect to its role in controlling outer mitochondrial membrane integrity. The effect of miR‑34a in PC12 cells has not yet been reported. In the present study, it was hypothesized that Bcl‑2 and SIRT1 may be critical downstream targets of miR‑34a that participate in apoptosis induction. miR‑34a mimics and inhibitors were transfected into PC12 cells, and the apoptosis and proliferation rates were compared between groups. It was demonstrated that induction of miR‑34a promotes apoptosis and senescence, inhibits proliferation, and leads to marked alterations in SIRT1, Bcl‑12 and acetyl (ac)‑p53 expression. These data indicate that miR‑34a may be important in neuropathy.

Show MeSH
Related in: MedlinePlus