Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G&gt;A

Alquézar, Carolina; Esteras, Noemí; Alzualde, Ainhoa; Moreno, Fermín; Ayuso, Matilde Sánchez; Munáin, Adolfo López de; Martín-Requero, Ángeles

doi:10.1371/journal.pone.0037057

Cited by 12 publications

(24 citation statements)

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“…44,46,54,[76][77][78][79] Altered activation of both TNF-α and WNT5A signalling has been found in the brains of patients with several types of neurodegenerative disorders. [80][81][82] Assuming that the TNF-α and WNT5A-mediated cell cycle dysfunction reported here could be peripheral sign of FTLD associated with PGRN deficiency, we think that targeting TNF-α and/or WNT5A signalling could have potential implications for designing novel therapeutic strategies.…”

Section: Resultsmentioning

confidence: 99%

“…Parametric tests were therefore used in the statistical analysis. Based on the expertise achieved in previous works 25,44,45 we expected that with the sample size that we used and the significance level that we established the variability within groups would be low enough and the power to detect differences between groups would be high enough to J Psychiatry Neurosci 2016;41(4) ensure a statistical power above 0.9. Statistical significance was estimated using the Student t test or, when appropriate, using 1-way and 2-way analyses of variance (ANOVA) followed by the Bonferroni test for multiple comparisons.…”

Section: Discussionmentioning

confidence: 99%

“…50 As already mentioned, PGRN-deficient lymphoblasts display increased levels and kinase activity of CDK6 protein. 44,45 On these grounds we considered the possibility that the enhanced CDK6 levels could contribute to increased NF-κB activity in these cell lines. Our results show that the treatment of PGRN-deficient cells with PD332991, a specific CDK6 kinase activity inhibitor, inhibited p65 NF-kB subunit phosphorylation, decreased WNT5A levels and blunted the enhanced proliferative response of the PGRN-deficient lymphoblasts.…”

Section: Discussionmentioning

confidence: 99%

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Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

Alquézar

Encarnación

Moreno

et al. 2016

jpn

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

Alquézar

Encarnación

Moreno

et al. 2016

jpn

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“…We had previously shown that PGRN deficit altered the activity of CDK4/6-associated kinase and survival of peripheral cells from FTLD-TDP patients bearing a GRN null mutation [29]. On these grounds, we were interested in evaluating the role of the CDK4/6/pRb pathway in the survival/death of control and PGRN-depleted neuroblastoma cell lines under serum deprivation conditions.…”

Section: Role Of Cdk4/6/prb Pathway On Cell Survivalmentioning

confidence: 99%

“…Previous work from this laboratory highlighted the role of the CDK6/retinoblastoma protein (pRb) pathway in controlling cell fate survival/death of peripheral cells from carriers of a loss-of-function GRN mutation, c.709-1G>A [29]. In this work, we have addressed the issue as to whether PGRN deficiency also modulates this cascade and eventually cell survival in a neuroblastoma cell line.…”

Section: Introductionmentioning

confidence: 99%

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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Aberrant TDP‐43 phosphorylation: a key wind gap from TDP‐43 to TDP‐43 proteinopathy

Huang¹,

Huang

et al. 2021

Ibrain

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TDP‐43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA‐binding protein of 43‐kDa molecular weight (TDP‐43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP‐43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP‐43 plays an important role in triggering or promoting the occurrence and progression of TDP‐43 proteinopathy. The hyperphosphorylation of TDP‐43 is undoubtedly an important factor in triggering or promoting the process of TDP‐43 proteinopathy. Hyperphosphorylation of TDP‐43 can inhibit the degradation of TDP‐43, aggravate the aggregation of TDP‐43 protein, increase the wrong localization of TDP‐43 in cells, and enhance the cytotoxicity of TDP‐43. More and more evidences show that the hyperphosphorylation of TDP‐43 plays an important role in the pathogenesis of TDP‐43 proteinopathy. Inhibition of TDP‐43 hyperphosphorylation may be one of the important strategies for the treatment of TDP‐43 proteinopathy. Therefore, this article reviews the role of TDP‐43 phosphorylation in TDP‐43 proteinopathy and the related mechanisms.

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Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

Cited by 12 publications

References 71 publications

Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers

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

Aberrant TDP‐43 phosphorylation: a key wind gap from TDP‐43 to TDP‐43 proteinopathy

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