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  1. Artikel ; Online: Caspase-resistant ROCK1 expression prolongs survival of Eµ-Myc B cell lymphoma mice.

    Mardilovich, Katerina / Naylor, Gregory / Julian, Linda / Phinichkusolchit, Narisa / Keeshan, Karen / Blyth, Karen / Olson, Michael F

    Disease models & mechanisms

    2024  Band 17, Heft 5

    Abstract: Apoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin-mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant ... ...

    Abstract Apoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin-mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant non-cleavable ROCK1 (Rock1 NC) prolonged survival of mice that rapidly develop B cell lymphomas due to Eµ-Myc transgene expression. Eµ-Myc; Rock1 NC mice had significantly fewer bone marrow cells relative to those in Eµ-Myc mice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower in Eµ-Myc; Rock1 NC mice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death in Eµ-Myc; Rock1 NC mouse bone marrows being more inflammatory. Rock1 WT recipient mice transplanted with pre-neoplastic Eµ-Myc; Rock1 NC bone marrow cells survived longer than mice transplanted with Eµ-Myc; Rock1 WT cells, indicating that the survival benefit was intrinsic to the Eµ-Myc; Rock1 NC bone marrow cells. The results suggest that the apoptotic death of Eµ-Myc; Rock1 NC cells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival.
    Mesh-Begriff(e) Animals ; rho-Associated Kinases/metabolism ; Lymphoma, B-Cell/pathology ; Lymphoma, B-Cell/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Caspases/metabolism ; Macrophages/metabolism ; Apoptosis ; Mice ; Survival Analysis ; Mice, Transgenic ; Bone Marrow Cells/metabolism ; Mice, Inbred C57BL ; Cell Cycle
    Chemische Substanzen Rock1 protein, mouse
    Sprache Englisch
    Erscheinungsdatum 2024-05-21
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.050631
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Hypoxia regulates insulin receptor substrate-2 expression to promote breast carcinoma cell survival and invasion.

    Mardilovich, Katerina / Shaw, Leslie M

    Cancer research

    2009  Band 69, Heft 23, Seite(n) 8894–8901

    Abstract: Insulin receptor substrate-2 (IRS-2) belongs to the IRS family of adaptor proteins that function as signaling intermediates for growth factor, cytokine, and integrin receptors, many of which have been implicated in cancer. Although the IRS proteins share ...

    Abstract Insulin receptor substrate-2 (IRS-2) belongs to the IRS family of adaptor proteins that function as signaling intermediates for growth factor, cytokine, and integrin receptors, many of which have been implicated in cancer. Although the IRS proteins share significant homology, distinct functions have been attributed to each family member in both normal and tumor cells. In cancer, IRS-2 is positively associated with aggressive tumor behavior. In the current study, we show that IRS-2 expression, but not IRS-1 expression, is positively regulated by hypoxia, which selects for tumor cells with increased metastatic potential. We identify IRS-2 as a novel hypoxia-responsive gene and establish that IRS-2 gene transcription increases in a hypoxia-inducible factor-dependent manner in hypoxic environments. IRS-2 is active to mediate insulin-like growth factor I-dependent signals in hypoxia, and enhanced activation of Akt in hypoxia is dependent on IRS-2 expression. Functionally, the elevated expression of IRS-2 facilitates breast carcinoma cell survival and invasion in hypoxia. Collectively, our results reveal a novel mechanism by which IRS-2 contributes to the aggressive behavior of hypoxic tumor cells.
    Mesh-Begriff(e) Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Hypoxia/physiology ; Cell Line, Tumor ; Cell Survival/physiology ; Female ; Humans ; Hypoxia-Inducible Factor 1/metabolism ; Insulin Receptor Substrate Proteins/biosynthesis ; Insulin Receptor Substrate Proteins/genetics ; Mammary Neoplasms, Experimental/genetics ; Mammary Neoplasms, Experimental/metabolism ; Mammary Neoplasms, Experimental/pathology ; Mice ; Neoplasm Invasiveness ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Transcription, Genetic
    Chemische Substanzen Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1 ; Insulin Receptor Substrate Proteins ; RNA, Messenger ; endothelial PAS domain-containing protein 1 (1B37H0967P)
    Sprache Englisch
    Erscheinungsdatum 2009-11-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-09-1152
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Targeting Rho GTPase signaling for cancer therapy.

    Mardilovich, Katerina / Olson, Michael F / Baugh, Mark

    Future oncology (London, England)

    2012  Band 8, Heft 2, Seite(n) 165–177

    Abstract: Accumulating evidence from basic and clinical studies supports the concept that signaling pathways downstream of Rho GTPases play important roles in tumor development and progression. As a result, there has been considerable interest in the possibility ... ...

    Abstract Accumulating evidence from basic and clinical studies supports the concept that signaling pathways downstream of Rho GTPases play important roles in tumor development and progression. As a result, there has been considerable interest in the possibility that specific proteins in these signal transduction pathways could be potential targets for cancer therapy. A number of inhibitors targeting critical effector proteins, activators or the Rho GTPases themselves, have been developed. We will review the strategies currently being used to develop inhibitors of Rho GTPases and downstream signaling kinases and discuss candidate entities. Although molecularly targeted drugs that inhibit Rho GTPase signaling have not yet been widely adopted for clinical use, their potential value as cancer therapeutics continues to drive considerable pharmaceutical research and development.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cytoskeleton/metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Guanine Nucleotide Exchange Factors/antagonists & inhibitors ; Humans ; Lim Kinases/antagonists & inhibitors ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Protein Processing, Post-Translational/drug effects ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Signal Transduction/drug effects ; p21-Activated Kinases/antagonists & inhibitors ; rho GTP-Binding Proteins/antagonists & inhibitors ; rho GTP-Binding Proteins/metabolism ; rho-Associated Kinases/antagonists & inhibitors
    Chemische Substanzen Antineoplastic Agents ; Enzyme Inhibitors ; Guanine Nucleotide Exchange Factors ; Lim Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1) ; rho GTP-Binding Proteins (EC 3.6.5.2)
    Sprache Englisch
    Erscheinungsdatum 2012-02
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2184533-5
    ISSN 1744-8301 ; 1479-6694
    ISSN (online) 1744-8301
    ISSN 1479-6694
    DOI 10.2217/fon.11.143
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Expression and function of the insulin receptor substrate proteins in cancer.

    Mardilovich, Katerina / Pankratz, Shannon L / Shaw, Leslie M

    Cell communication and signaling : CCS

    2009  Band 7, Seite(n) 14

    Abstract: The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not ... ...

    Abstract The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not contain any intrinsic kinase activity, but rather serve as scaffolds to organize signaling complexes and initiate intracellular signaling pathways. As common intermediates of multiple receptors that can influence tumor progression, the IRS proteins are positioned to play a pivotal role in regulating the response of tumor cells to many different microenvironmental stimuli. Limited studies on IRS expression in human tumors and studies on IRS function in human tumor cell lines and in mouse models have provided clues to the potential function of these adaptor proteins in human cancer. A general theme arises from these studies; IRS-1 and IRS-4 are most often associated with tumor growth and proliferation and IRS-2 is most often associated with tumor motility and invasion. In this review, we discuss the mechanisms by which IRS expression and function are regulated and how the IRS proteins contribute to tumor initiation and progression.
    Sprache Englisch
    Erscheinungsdatum 2009-06-17
    Erscheinungsland England
    Dokumenttyp Journal Article
    ISSN 1478-811X
    ISSN (online) 1478-811X
    DOI 10.1186/1478-811X-7-14
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Expression and function of the insulin receptor substrate proteins in cancer

    Pankratz Shannon L / Mardilovich Katerina / Shaw Leslie M

    Cell Communication and Signaling, Vol 7, Iss 1, p

    2009  Band 14

    Abstract: Abstract The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do ... ...

    Abstract Abstract The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not contain any intrinsic kinase activity, but rather serve as scaffolds to organize signaling complexes and initiate intracellular signaling pathways. As common intermediates of multiple receptors that can influence tumor progression, the IRS proteins are positioned to play a pivotal role in regulating the response of tumor cells to many different microenvironmental stimuli. Limited studies on IRS expression in human tumors and studies on IRS function in human tumor cell lines and in mouse models have provided clues to the potential function of these adaptor proteins in human cancer. A general theme arises from these studies; IRS-1 and IRS-4 are most often associated with tumor growth and proliferation and IRS-2 is most often associated with tumor motility and invasion. In this review, we discuss the mechanisms by which IRS expression and function are regulated and how the IRS proteins contribute to tumor initiation and progression.
    Schlagwörter Medicine ; R ; Cytology ; QH573-671
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2009-06-01T00:00:00Z
    Verlag BMC
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation.

    Mardilovich, Katerina / Gabrielsen, Mads / McGarry, Lynn / Orange, Clare / Patel, Rachana / Shanks, Emma / Edwards, Joanne / Olson, Michael F

    Molecular cancer therapeutics

    2014  Band 14, Heft 1, Seite(n) 246–258

    Abstract: Prostate cancer affects a large proportion of the male population, and is primarily driven by androgen receptor (AR) activity. First-line treatment typically consists of reducing AR signaling by hormone depletion, but resistance inevitably develops over ... ...

    Abstract Prostate cancer affects a large proportion of the male population, and is primarily driven by androgen receptor (AR) activity. First-line treatment typically consists of reducing AR signaling by hormone depletion, but resistance inevitably develops over time. One way to overcome this issue is to block AR function via alternative means, preferably by inhibiting protein targets that are more active in tumors than in normal tissue. By staining prostate cancer tumor sections, elevated LIM kinase 1 (LIMK1) expression and increased phosphorylation of its substrate Cofilin were found to be associated with poor outcome and reduced survival in patients with nonmetastatic prostate cancer. A LIMK-selective small molecule inhibitor (LIMKi) was used to determine whether targeted LIMK inhibition was a potential prostate cancer therapy. LIMKi reduced prostate cancer cell motility, as well as inhibiting proliferation and increasing apoptosis in androgen-dependent prostate cancer cells more effectively than in androgen-independent prostate cancer cells. LIMK inhibition blocked ligand-induced AR nuclear translocation, reduced AR protein stability and transcriptional activity, consistent with its effects on proliferation and survival acting via inhibition of AR activity. Furthermore, inhibition of LIMK activity increased αTubulin acetylation and decreased AR interactions with αTubulin, indicating that the role of LIMK in regulating microtubule dynamics contributes to AR function. These results indicate that LIMK inhibitors could be beneficial for the treatment of prostate cancer both by reducing nuclear AR translocation, leading to reduced proliferation and survival, and by inhibiting prostate cancer cell dissemination.
    Mesh-Begriff(e) Actin Depolymerizing Factors/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Nucleus/metabolism ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lim Kinases/antagonists & inhibitors ; Lim Kinases/genetics ; Lim Kinases/metabolism ; Male ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/mortality ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Small Molecule Libraries/pharmacology ; Survival Analysis ; Tubulin/genetics ; Tubulin/metabolism
    Chemische Substanzen AR protein, human ; Actin Depolymerizing Factors ; Receptors, Androgen ; Small Molecule Libraries ; Tubulin ; LIMK1 protein, human (EC 2.7.11.1) ; LIMK2 protein, human (EC 2.7.11.1) ; Lim Kinases (EC 2.7.11.1)
    Sprache Englisch
    Erscheinungsdatum 2014-10-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-14-0447
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.

    Mardilovich, Katerina / Baugh, Mark / Crighton, Diane / Kowalczyk, Dominika / Gabrielsen, Mads / Munro, June / Croft, Daniel R / Lourenco, Filipe / James, Daniel / Kalna, Gabriella / McGarry, Lynn / Rath, Oliver / Shanks, Emma / Garnett, Mathew J / McDermott, Ultan / Brookfield, Joanna / Charles, Mark / Hammonds, Tim / Olson, Michael F

    Oncotarget

    2015  Band 6, Heft 36, Seite(n) 38469–38486

    Abstract: The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome ...

    Abstract The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy.
    Mesh-Begriff(e) Breast Neoplasms/drug therapy ; Breast Neoplasms/enzymology ; Breast Neoplasms/pathology ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/enzymology ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Humans ; Lim Kinases/antagonists & inhibitors ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Lung Neoplasms/pathology ; MCF-7 Cells ; Microtubules/metabolism ; Mitosis/drug effects ; Mitosis/physiology ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/pathology ; Neuroblastoma/drug therapy ; Neuroblastoma/enzymology ; Neuroblastoma/pathology
    Chemische Substanzen Lim Kinases (EC 2.7.11.1)
    Sprache Englisch
    Erscheinungsdatum 2015-11-05
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.6288
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel: Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein.

    Tang, Wan-Yee / Newbold, Retha / Mardilovich, Katerina / Jefferson, Wendy / Cheng, Robert Y S / Medvedovic, Mario / Ho, Shuk-Mei

    Endocrinology

    2008  Band 149, Heft 12, Seite(n) 5922–5931

    Abstract: Neonatal exposure of CD-1 mice to diethylstilbestrol (DES) or genistein (GEN) induces uterine adenocarcinoma in aging animals. Uterine carcinogenesis in this model is ovarian dependent because its evolution is blocked by prepubertal ovariectomy. This ... ...

    Abstract Neonatal exposure of CD-1 mice to diethylstilbestrol (DES) or genistein (GEN) induces uterine adenocarcinoma in aging animals. Uterine carcinogenesis in this model is ovarian dependent because its evolution is blocked by prepubertal ovariectomy. This study seeks to discover novel uterine genes whose expression is altered by such early endocrine disruption via an epigenetic mechanism. Neonatal mice were treated with 1 or 1000 microg/kg DES, 50 mg/kg GEN, or oil (control) on d 1-5. One group of treated mice was killed before puberty on d 19. Others were ovariectomized or left intact, and killed at 6 and 18 months of age. Methylation-sensitive restriction fingerprinting was performed to identify differentially methylated sequences associated with neonatal exposure to DES/GEN. Among 14 candidates, nucleosomal binding protein 1 (Nsbp1), the gene for a nucleosome-core-particle binding protein, was selected for further study because of its central role in chromatin remodeling. In uteri of immature control mice, Nsbp1 promoter CpG island (CGI) was minimally methylated. Once control mice reached puberty, the Nsbp1 CGI became hypermethylated, and gene expression declined further. In contrast, in neonatal DES/GEN-treated mice, the Nsbp1 CGI stayed anomalously hypomethylated, and the gene exhibited persistent overexpression throughout life. However, if neonatal DES/GEN-treated mice were ovariectomized before puberty, the CGI remained minimally to moderately methylated, and gene expression was subdued except in the group treated with 1000 microg/kg DES. Thus, the life reprogramming of uterine Nsbp1 expression by neonatal DES/GEN exposure appears to be mediated by an epigenetic mechanism that interacts with ovarian hormones in adulthood.
    Mesh-Begriff(e) Animals ; Animals, Newborn ; Cluster Analysis ; DNA Methylation/drug effects ; Diethylstilbestrol/pharmacology ; Female ; Gene Expression/drug effects ; Genistein/pharmacology ; HMGN Proteins/genetics ; Male ; Mice ; Ovariectomy ; Promoter Regions, Genetic/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Uterus/drug effects ; Uterus/metabolism
    Chemische Substanzen HMGN Proteins ; Diethylstilbestrol (731DCA35BT) ; Genistein (DH2M523P0H)
    Sprache Englisch
    Erscheinungsdatum 2008-07-31
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/en.2008-0682
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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