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  • Springer Science and Business Media LLC  (9)
  • 1
    Online Resource
    Online Resource
    Cdk5 regulates IP3R1-mediated Ca2+ dynamics and Ca2+-mediated cell proliferation
    Springer Science and Business Media LLC ; 2022
    In:  Cellular and Molecular Life Sciences Vol. 79, No. 9 ( 2022-09)
    Details
    In: Cellular and Molecular Life Sciences, Springer Science and Business Media LLC, Vol. 79, No. 9 ( 2022-09)
    Abstract: Loss of cyclin-dependent kinase 5 (Cdk5) in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) increases ER–mitochondria tethering and ER Ca 2+ transfer to the mitochondria, subsequently increasing mitochondrial Ca 2+ concentration ([Ca 2+ ] mt ). This suggests a role for Cdk5 in regulating intracellular Ca 2+ dynamics, but how Cdk5 is involved in this process remains to be explored. Using ex vivo primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5 −/− mouse embryos, we show here that loss of Cdk5 causes an increase in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ), which is not due to reduced internal Ca 2+ store capacity or increased Ca 2+ influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca 2+ from internal stores, we determined that the rise in [Ca 2+ ] cyt in Cdk5 −/− MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca 2+ release from internal stores. Cdk5 interacts with the IP3R1 Ca 2+ channel and phosphorylates it at Ser 421 . Such phosphorylation controls IP3R1-mediated Ca 2+ release as loss of Cdk5, and thus, loss of IP3R1 Ser 421 phosphorylation triggers an increase in IP3R1-mediated Ca 2+ release in Cdk5 −/− MEFs, resulting in elevated [Ca 2+ ] cyt . Elevated [Ca 2+ ] cyt in these cells further induces the production of reactive oxygen species (ROS), which upregulates the levels of Nrf2 and its targets, Prx1 and Prx2. Cdk5 −/− MEFs, which have elevated [Ca 2+ ] cyt , proliferate at a faster rate compared to wt, and Cdk5 −/− embryos have increased body weight and size compared to their wt littermates. Taken together, we show that altered IP3R1-mediated Ca 2+ dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5 −/− embryos.
    Type of Medium: Online Resource
    ISSN: 1420-682X , 1420-9071
    URL: Article
    DOI: 10.1007/s00018-022-04515-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1458497-9
    SSG: 12
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Integration of a bacterial gene sequence into a chronic eosinophilic leukemia patient’s genome as part of a fusion gene linker
    Springer Science and Business Media LLC ; 2017
    In:  Biomarker Research Vol. 5, No. 1 ( 2017-12)
    Details
    In: Biomarker Research, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2017-12)
    Type of Medium: Online Resource
    ISSN: 2050-7771
    URL: Article
    DOI: 10.1186/s40364-017-0101-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2699926-2
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  • 3
    Online Resource
    Online Resource
    Cyclin E in breast tumors is cleaved into its low molecular weight forms by calpain
    Springer Science and Business Media LLC ; 2003
    In:  Oncogene Vol. 22, No. 5 ( 2003-02-06), p. 769-774
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 22, No. 5 ( 2003-02-06), p. 769-774
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/sj.onc.1206166
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2003
    detail.hit.zdb_id: 2008404-3
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  • 4
    Online Resource
    Online Resource
    Neutrophil TLR4 and PKR are targets of breast cancer cell glycosaminoglycans and effectors of glycosaminoglycan-induced APRIL secretion
    Springer Science and Business Media LLC ; 2018
    In:  Oncogenesis Vol. 7, No. 6 ( 2018-06-15)
    Details
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 7, No. 6 ( 2018-06-15)
    Abstract: A proliferation-inducing ligand (APRIL), which induces survival and migration signals and tumor growth, is commonly observed in breast cancer tissues but is not often expressed in breast cancer cells themselves. Here, we examined whether breast cancer cells induce APRIL secretion from neutrophils, which are frequently recruited into the breast tumor microenvironment. We found that breast cancer cells do stimulate neutrophils to secrete APRIL through their glycosaminoglycans. Breast cancer cells depleted of heparan sulfate or chondroitin sulfate glycosaminoglycans lose their ability to induce APRIL secretion from neutrophils, and heparan sulfate and chondroitin sulfate can induce secretion that is comparable to that of breast cancer cell-induced secretion. While stimulation of the RNA-activated protein kinase (PKR) is sufficient to induce neutrophil APRIL secretion, both PKR and the toll-like receptor 4 (TLR4) are required for breast cancer cell glycosaminoglycan-induced secretion as separate and specific inhibition of TLR4 or PKR completely prevents the process, suggesting that breast cancer cell glycosaminoglycans target neutrophil TLR4 and PKR to trigger APRIL secretion. Thus, apart from the putative role of cell surface heparan sulfate in binding APRIL that leads to cell growth, we demonstrate that heparan sulfate, as well as chondroitin sulfate plays a novel role in promoting neutrophil secretion of APRIL that could lead to further cell growth. We propose that breast cancer cells take advantage of the neutrophil recruitment to the tumor microenvironment through the dual role of heparan sulfate as cell surface receptor or docking molecule for APRIL and as a ligand that induces neutrophil APRIL secretion to promote their own growth.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    URL: Article
    DOI: 10.1038/s41389-018-0058-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2674437-5
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  • 5
    Online Resource
    Online Resource
    Loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death through dysregulation of the mitochondrial permeability transition pore
    Springer Science and Business Media LLC ; 2018
    In:  Oncogene Vol. 37, No. 13 ( 2018-03-29), p. 1788-1804
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 37, No. 13 ( 2018-03-29), p. 1788-1804
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-017-0103-1
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2008404-3
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  • 6
    Online Resource
    Online Resource
    d,l-Methadone causes leukemic cell apoptosis via an OPRM1-triggered increase in IP3R-mediated ER Ca2+ release and decrease in Ca2+ efflux, elevating [Ca2+]i
    Springer Science and Business Media LLC ; 2021
    In:  Scientific Reports Vol. 11, No. 1 ( 2021-01-13)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-01-13)
    Abstract: The search continues for improved therapy for acute lymphoblastic leukemia ( a LL), the most common malignancy in children. Recently, d , l -methadone was put forth as sensitizer for a LL chemotherapy. However, the specific target of d , l -methadone in leukemic cells and the mechanism by which it induces leukemic cell apoptosis remain to be defined. Here, we demonstrate that d , l -methadone induces leukemic cell apoptosis through activation of the mu1 subtype of opioid receptors (OPRM1). d , l -Methadone evokes IP3R-mediated ER Ca 2+ release that is inhibited by OPRM1 loss. In addition, the rate of Ca 2+ extrusion following d , l -methadone treatment is reduced, but is accelerated by loss of OPRM1. These d , l -methadone effects cause a lethal rise in [Ca 2+ ] i that is again inhibited by OPRM1 loss, which then prevents d , l -methadone-induced apoptosis that is associated with activation of calpain-1, truncation of Bid, cytochrome C release, and proteolysis of caspase-3/12. Chelating intracellular Ca 2+ with BAPTA-AM reverses d , l -methadone-induced apoptosis, establishing a link between the rise in [Ca 2+ ] i and d , l -methadone-induced apoptosis. Altogether, our findings point to OPRM1 as a specific target of d , l -methadone in leukemic cells, and that OPRM1 activation by d , l -methadone disrupts IP3R-mediated ER Ca 2+ release and rate of Ca 2+ efflux, causing a rise in [Ca 2+ ] i that upregulates the calpain-1-Bid-cytochrome C-caspase-3/12 apoptotic pathway.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-80520-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2615211-3
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  • 7
    Online Resource
    Online Resource
    Tyrosine hydroxylase expression and Cdk5 kinase activity in ataxic cerebellum
    Springer Science and Business Media LLC ; 2008
    In:  Molecular and Cellular Biochemistry Vol. 318, No. 1-2 ( 2008-11), p. 7-12
    Details
    In: Molecular and Cellular Biochemistry, Springer Science and Business Media LLC, Vol. 318, No. 1-2 ( 2008-11), p. 7-12
    Type of Medium: Online Resource
    ISSN: 0300-8177 , 1573-4919
    URL: Article
    DOI: 10.1007/s11010-008-9850-1
    RVK:
    WD 5725
    RVK:
    WD 5275
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2003615-2
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    mPTP opening caused by Cdk5 loss is due to increased mitochondrial Ca2+ uptake
    Springer Science and Business Media LLC ; 2020
    In:  Oncogene Vol. 39, No. 13 ( 2020-03-26), p. 2797-2806
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 39, No. 13 ( 2020-03-26), p. 2797-2806
    Abstract: We previously demonstrated that loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death by inducing mitochondrial permeability transition pore (mPTP) opening (Oncogene 37, 1788–1804). However, the molecular mechanism by which Cdk5 loss causes mPTP opening remains to be investigated. Using primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5 −/− mouse embryos, we show that absence of Cdk5 causes a significant increase in both mPTP opening and mitochondrial Ca 2+ level. Analysis of subcellular fractions of MEFs demonstrates that Cdk5 localizes in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and Cdk5 loss in MAMs causes increased ER-mitochondria tethering, a process required for Ca 2+ transfer from the ER to the mitochondria. Loss of Cdk5 also causes increased ATP-mediated mitochondrial Ca 2+ uptake from the ER. Inhibition of ER Ca 2+ release or mitochondrial Ca 2+ uptake in Cdk5 −/− MEFs prevents mPTP opening, indicating that mPTP opening in Cdk5 −/− MEFs is due to increased Ca 2+ transfer from the ER to the mitochondria. Altogether, our findings suggest that Cdk5 in MAMs regulates mitochondrial Ca 2+ homeostasis that is disturbed upon Cdk5 loss, which leads to mPTP opening.
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/s41388-020-1188-5
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2008404-3
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  • 9
    Online Resource
    Online Resource
    CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway
    Springer Science and Business Media LLC ; 2021
    In:  Cell Death & Disease Vol. 13, No. 1 ( 2021-12-20)
    Details
    In: Cell Death & Disease, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12-20)
    Abstract: Developmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2 an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-β-gal staining compared to Cdk5rap2 +/+ and Cdk5rap2 +/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3β, causing increased inhibitory GSK3β Ser9 phosphorylation and inhibiting the activity of GSK3β, which phosphorylates β-catenin, tagging β-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing nuclear β-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or β-catenin causes WIP1 downregulation. Inhibition of GSK3β activity restores β-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3β activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3β/β-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.
    Type of Medium: Online Resource
    ISSN: 2041-4889
    URL: Article
    DOI: 10.1038/s41419-021-04457-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2541626-1
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