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  1. Article: Class IIA HDACs in the regulation of neurodegeneration.

    Majdzadeh, Nazanin / Morrison, Brad E / D'Mello, Santosh R

    Frontiers in bioscience : a journal and virtual library

    2008  Volume 13, Page(s) 1072–1082

    Abstract: Neurodegenerative diseases affect millions of patients annually and are a significant burden on the health care systems around the world. While there are symptomatic remedies for patients suffering from various neurodegenerative diseases, there are no ... ...

    Abstract Neurodegenerative diseases affect millions of patients annually and are a significant burden on the health care systems around the world. While there are symptomatic remedies for patients suffering from various neurodegenerative diseases, there are no cures as of today. Cell death by apoptosis is a common hallmark of neurodegeneration. Therefore, deciphering the molecular pathways regulating this process is of significant value to scientists' endeavor to understand neurodegenerative disorders. Efforts along these lines have uncovered a number of molecular pathways that regulate neuronal apoptosis. Recently, a family of proteins known as histone deacetylases (HDACs) has been linked to regulation of cell survival as well as death. The focus of this review is to summarize our current understanding of the role of HDACs and in particular a subgroup of proteins in this family classified as class IIa HDACs in the regulation of neuronal cell death. It is apparent based on the information presented in this review that although very similar in their primary sequence, members of this family of proteins often have distinct roles in orchestrating apoptotic cell death in the brain.
    MeSH term(s) Animals ; Apoptosis ; Catalysis ; Cell Cycle ; Cell Differentiation ; Enzyme Inhibitors/pharmacology ; Histone Deacetylase Inhibitors ; Histone Deacetylases/metabolism ; Humans ; Models, Biological ; Nerve Degeneration ; Neurodegenerative Diseases/metabolism ; Neurons/metabolism ; Phosphorylation ; Protein Structure, Tertiary
    Chemical Substances Enzyme Inhibitors ; Histone Deacetylase Inhibitors ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2008-01-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2141320-4
    ISSN 1093-9946
    ISSN 1093-9946
    DOI 10.2741/2745
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5867: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article: Inhibition of GSK3beta is a common event in neuroprotection by different survival factors.

    Chin, Paul C / Majdzadeh, Nazanin / D'Mello, Santosh R

    Brain research. Molecular brain research

    2005  Volume 137, Issue 1-2, Page(s) 193–201

    Abstract: Depolarizing concentrations of potassium (HK, 25 mM), cyclic AMP elevating agents and analogs (cAMP), insulin-like growth factor-1 (IGF-1), or lithium can maintain the survival of cultured rat cerebellar granule neurons (CGNs). We investigated the ... ...

    Abstract Depolarizing concentrations of potassium (HK, 25 mM), cyclic AMP elevating agents and analogs (cAMP), insulin-like growth factor-1 (IGF-1), or lithium can maintain the survival of cultured rat cerebellar granule neurons (CGNs). We investigated the possibility that the signal transduction pathways utilized by these four survival factors converge in regulating a common molecular target. We targeted the regulation of the kinase GSK3beta as the critical event in the survival directed by the four survival factors. We found that treatment of CGNs with HK, the cAMP-elevating agent forskolin, IGF-1, and lithium resulted in phosphorylation of GSK3beta at serine-9 and thus its inactivation. Furthermore, pharmacological inhibition of core components in the survival signaling cascades initiated by HK, forskolin, IGF-1, and lithium causes apoptosis and activation of GSK3beta accompanies this death. Finally, we examined the pharmacological inhibitors of GSK3beta, GSK3 inhibitor I, TDZD-8, and SB-415286, for their ability to prevent low potassium (LK)-induced apoptosis. Although previous reports demonstrate inhibition of GSK3beta in in vitro kinase assays with GSK3 inhibitor I and TDZD-8, we were unable to detect inhibition of GSK3beta in neuronal cultures treated with these compounds and thus no protection from LK-induced apoptosis. SB-415286 on the other hand, was able to rescue CGNs from cell death. Taken together, we conclude that regulation of GSK3beta is a critical convergence event in the promotion of CGN survival by different factors.
    MeSH term(s) Aminophenols/pharmacology ; Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Cell Survival/drug effects ; Cell Survival/physiology ; Cells, Cultured ; Cerebellar Cortex/metabolism ; Colforsin/pharmacology ; Cyclic AMP/agonists ; Cyclic AMP/metabolism ; Cytoprotection/drug effects ; Cytoprotection/physiology ; Enzyme Inhibitors/pharmacology ; Glycogen Synthase Kinase 3/drug effects ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Insulin-Like Growth Factor I/pharmacology ; Lithium/pharmacology ; Maleimides/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Neuroprotective Agents/metabolism ; Neuroprotective Agents/pharmacology ; Potassium/metabolism ; Potassium/pharmacology ; Rats
    Chemical Substances 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione ; Aminophenols ; Enzyme Inhibitors ; Maleimides ; Neuroprotective Agents ; Colforsin (1F7A44V6OU) ; Insulin-Like Growth Factor I (67763-96-6) ; Lithium (9FN79X2M3F) ; Cyclic AMP (E0399OZS9N) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Gsk3b protein, rat (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2005-06-13
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 632883-0
    ISSN 1872-6941 ; 0169-328X
    ISSN (online) 1872-6941
    ISSN 0169-328X
    DOI 10.1016/j.molbrainres.2005.03.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2181: Show issues Location:
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  3. Article: HDAC4 inhibits cell-cycle progression and protects neurons from cell death.

    Majdzadeh, Nazanin / Wang, Lulu / Morrison, Brad E / Bassel-Duby, Rhonda / Olson, Eric N / D'Mello, Santosh R

    Developmental neurobiology

    2008  Volume 68, Issue 8, Page(s) 1076–1092

    Abstract: HDAC4 is a Class II histone deacetylase (HDAC) that is highly expressed in the brain, but whose functional significance in the brain is not known. We show that forced expression of HDAC4 in cerebellar granule neurons protects them against low potassium- ... ...

    Abstract HDAC4 is a Class II histone deacetylase (HDAC) that is highly expressed in the brain, but whose functional significance in the brain is not known. We show that forced expression of HDAC4 in cerebellar granule neurons protects them against low potassium-induced apoptosis. HDAC4 also protects HT22 neuroblastoma cells from death induced by oxidative stress. HDAC4-mediated neuroprotection does not require its HDAC catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Neuroprotection by HDAC4 also does not require the Raf-MEK-ERK or the PI-3 kinase-Akt signaling pathways and occurs despite the activation of c-jun, an event that is generally believed to condemn neurons to die. The protective action of HDAC4 occurs in the nucleus and is mediated by a region that contains the nuclear localization signal. HDAC4 inhibits the activity of cyclin-dependent kinase-1 (CDK1) and the progression of proliferating HEK293T and HT22 cells through the cell cycle. Mice-lacking HDAC4 have elevated CDK1 activity and display cerebellar abnormalities including a progressive loss of Purkinje neurons postnatally in posterior lobes. Surviving Purkinje neurons in these lobes have duplicated soma. Furthermore, large numbers of cells within these affected lobes incorporate BrdU, indicating cell-cycle progression. These abnormalities along with the ability of HDAC4 to inhibit CDK1 and cell-cycle progression in cultured cells suggest that neuroprotection by HDAC4 is mediated by preventing abortive cell-cycle progression.
    MeSH term(s) Adenoviridae/genetics ; Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Blotting, Western ; CDC2 Protein Kinase/metabolism ; Cell Cycle/physiology ; Cell Line ; Cell Line, Tumor ; Cerebellar Cortex/cytology ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Histone Deacetylases/physiology ; Humans ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Neurons/cytology ; Neurons/metabolism ; Neurons/physiology ; Plasmids/genetics ; Potassium/toxicity ; Purkinje Cells/cytology ; Purkinje Cells/metabolism ; Purkinje Cells/physiology ; Rats ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Repressor Proteins/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Transfection
    Chemical Substances Repressor Proteins ; Green Fluorescent Proteins (147336-22-9) ; CDC2 Protein Kinase (EC 2.7.11.22) ; HDAC4 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2008-05-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2256184-5
    ISSN 1097-4695 ; 1932-8451 ; 0022-3034
    ISSN (online) 1097-4695
    ISSN 1932-8451 ; 0022-3034
    DOI 10.1002/dneu.20637
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 853: Show issues Location:
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  4. Article: Neuroprotection by histone deacetylase-related protein.

    Morrison, Brad E / Majdzadeh, Nazanin / Zhang, Xiaoguang / Lyles, Aaron / Bassel-Duby, Rhonda / Olson, Eric N / D'Mello, Santosh R

    Molecular and cellular biology

    2006  Volume 26, Issue 9, Page(s) 3550–3564

    Abstract: The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons ... ...

    Abstract The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun phosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.
    MeSH term(s) Animals ; Apoptosis ; Cell Nucleus/enzymology ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Histone Deacetylase Inhibitors ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mice ; Neurons/cytology ; Neurons/drug effects ; Neurons/enzymology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Proto-Oncogene Proteins c-jun/genetics ; Proto-Oncogene Proteins c-jun/metabolism ; RNA, Messenger/metabolism ; Rats ; Transcription, Genetic
    Chemical Substances Enzyme Inhibitors ; Histone Deacetylase Inhibitors ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-jun ; RNA, Messenger ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2006-04-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.26.9.3550-3564.2006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1666: Show issues Location:
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  5. Article: Inhibition of neuronal apoptosis by the cyclin-dependent kinase inhibitor GW8510: identification of 3' substituted indolones as a scaffold for the development of neuroprotective drugs.

    Johnson, Kyle / Liu, Li / Majdzadeh, Nazanin / Chavez, Cindy / Chin, Paul C / Morrison, Brad / Wang, Lulu / Park, Jane / Chugh, Priti / Chen, Hsin-Mei / D'Mello, Santosh R

    Journal of neurochemistry

    2005  Volume 93, Issue 3, Page(s) 538–548

    Abstract: Increasing evidence suggests that neuronal apoptosis is triggered by the inappropriate activation of cyclin-dependent kinases leading to an abortive re-entry of neurons into the cell cycle. Pharmacological inhibitors of cell-cycle progression may ... ...

    Abstract Increasing evidence suggests that neuronal apoptosis is triggered by the inappropriate activation of cyclin-dependent kinases leading to an abortive re-entry of neurons into the cell cycle. Pharmacological inhibitors of cell-cycle progression may therefore have value in the treatment of neurodegenerative diseases in humans. GW8510 is a 3' substituted indolone that was developed recently as an inhibitor of cyclin-dependent kinase 2 (CDK2). We found that GW8510 inhibits the death of cerebellar granule neurons caused by switching them from high potassium (HK) medium to low potassium (LK) medium. Although GW8510 inhibits CDK2 and other CDKs when tested in in vitro biochemical assays, when used on cultured neurons it only inhibits CDK5, a cytoplasmic CDK that is not associated with cell-cycle progression. Treatment of cultured HEK293T cells with GW8510 does not inhibit cell-cycle progression, consistent with its inability to inhibit mitotic CDKs in intact cells. Neuroprotection by GW8510 is independent of Akt and MEK-ERK signaling. Furthermore, GW8510 does not block the LK-induced activation of Gsk3beta and, while inhibiting c-jun phosphorylation, does not inhibit the increase in c-jun expression observed in apoptotic neurons. We also examined the effectiveness of other 3' substituted indolone compounds to protect against neuronal apoptosis. We found that like GW8510, the VEGF Receptor 2 Kinase Inhibitors [3-(1H-pyrrol-2-ylmethylene)-1,3-dihydroindol-2-one], {(Z)-3-[2,4-Dimethyl-3-(ethoxycarbonyl)pyrrol-5-yl)methylidenyl]indol-2-one} and [(Z)-5-Bromo-3-(4,5,6,6-tetrahydro-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one], the Src family kinase inhibitor SU6656 and a commercially available inactive structural analog of an RNA-dependent protein kinase inhibitor 5-Chloro-3-(3,5-dichloro-4-hydroxybenzylidene)-1,3-dihydro-indol-2-one, are all neuroprotective when tested on LK-treated neurons. Along with our recent identification of the c-Raf inhibitor GW5074 (also a 3' substituted indolone) as a neuroprotective compound, our findings identify the 3' substituted indolone as a core structure for the designing of neuroprotective drugs that may be used to treat neurodegenerative diseases in humans.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Cell Line ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cyclin-Dependent Kinases/metabolism ; Dose-Response Relationship, Drug ; Indoles/chemistry ; Indoles/pharmacology ; Neurons/drug effects ; Neurons/enzymology ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/pharmacology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Wistar
    Chemical Substances GW8510 ; Indoles ; Neuroprotective Agents ; Protein Kinase Inhibitors ; Cyclin-Dependent Kinases (EC 2.7.11.22)
    Language English
    Publishing date 2005-05
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/j.1471-4159.2004.03004.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui II Zs.170: Show issues Location:
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