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  • 1.
    Brännvall, Karin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Hormonal Regulation of Neural Stem Cell Proliferation and Fate Determination2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stem cells have the capacity for both self renewal, and to form all cell types in the body. Interestingly, so called neural stem cells (NSCs) are found in the adult human brain, which is of significance both out of a developmental perspective and from a clinical point of view. At the present moment, the regulation of neural stem cell (NSC) proliferation and fate determination is not completely understood.

    The overall aim of this thesis was to study the mechanisms that regulate NSC proliferation and fate determination in vitro and in vivo. In particular, the roles of the female sex hormone estrogen and the testosterone analogue nandrolone, as well as the melanocortin α-melanocyte stimulating hormone (α-MSH), were analyzed in this context. Also, the breast cancer susceptibility gene one (BRCA-1), was studied in the brain with emphasis on regions containing NSCs.

    Our findings show that estrogen and nandrolone have similar effects on NSCs; both decreased NSC proliferation and increased neurogenesis. Estrogen's ability to reduce proliferation was due to increased levels of p21, an inhibitor of cyclin dependent kinases. In contrast, no change in p21 was observed in the case of nandrolone, indicating differential regulation. Adult rats subjected to nandrolone injections had 30% reduced NSC proliferation in the dentate gyrus, indicating profound effects on NSCs in vivo.

    The melanocortin α-MSH acted as a mitogen by increasing levels of cyclinD1 and retinoblastoma protein; as a result NSC proliferation was doubled.

    Finally, BRCA-1 is expressed while NSCs proliferate, but is drastically down regulated upon differentiation, indicating that BRCA-1 could be used as a possible NSC marker.

    In summary, in this thesis estrogen and nandrolone were identified as NSC regulators which decrease proliferation and positively influence neurogenesis. Also, we have identified the hormone α-MSH as a NSC mitogen, and BRCA-1 as a possible NSC marker.

    List of papers
    1. Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation
    Open this publication in new window or tab >>Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation
    2002 In: Molecular Cellular Neuroscience, Vol. 21, no 3, p. 512-20Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92444 (URN)
    Available from: 2004-11-25 Created: 2004-11-25Bibliographically approved
    2. Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation
    Open this publication in new window or tab >>Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation
    2003 In: Journal of Neuroscience Research, Vol. 71, no 6, p. 769-76Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92445 (URN)
    Available from: 2004-11-25 Created: 2004-11-25Bibliographically approved
    3. 19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain
    Open this publication in new window or tab >>19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain
    In: European Journal of NeuroscienceArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92446 (URN)
    Available from: 2004-11-25 Created: 2004-11-25Bibliographically approved
    4. α-MSH dependent regulation of neural stem cell proliferation
    Open this publication in new window or tab >>α-MSH dependent regulation of neural stem cell proliferation
    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92447 (URN)
    Available from: 2004-11-25 Created: 2004-11-25 Last updated: 2011-01-11Bibliographically approved
  • 2.
    Brännvall, Karin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Bogdanovic, Nenad
    Lindholm, Dan
    19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brainIn: European Journal of NeuroscienceArticle in journal (Refereed)
  • 3.
    Brännvall, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cellular Neurobiology.
    Ingvarsson, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindholm, Dan
    α-MSH dependent regulation of neural stem cell proliferationManuscript (Other academic)
  • 4.
    Brännvall, Karin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Korhonen, Laura
    Lindholm, Dan
    Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation2002In: Molecular Cellular Neuroscience, Vol. 21, no 3, p. 512-20Article in journal (Refereed)
  • 5.
    Brännvall, Karin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Korhonen, Laura
    Skoglösa, Ylva
    Lindholm, Dan
    Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation2003In: Journal of Neuroscience Research, Vol. 71, no 6, p. 769-76Article in journal (Refereed)
  • 6. Martinez-Maza, Rodrigo
    et al.
    Steen, Håkan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Sokka, Anna-Leena
    Arumae, Urmas
    Andersson, Leif C.
    Korhonen, Laura
    Lindholm, Dan
    G-protein pathway suppressor 2 protein induces cell death by activating caspase-3 and inhibits XIAP in vitroManuscript (Other academic)
  • 7.
    Steen, Håkan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Novel Interactors of X-linked Inhibitor of Apoptosis Protein: Expression and Effects on Tumor Cell Death2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Programmed cell death, or apoptosis, has during the last decade received a lot of attention due to its involvement in a large number of pathological conditions. Since death is always irreversible, it is important for cells to fully control the initiation and execution of this process. One of many apoptosis-regulatory proteins is XIAP, which blocks the action of caspases, a family of proteases that are important during apoptosis. However, apoptosis inhibitors have to be tightly controlled since too little cell death can lead to the development of tumors and other diseases. This thesis is the result of an aspiration to fully understand the function and regulation of XIAP.

    By using the yeast-2-hybrid system, we identified two novel binding partners of XIAP. The first, GPS2, was found to bind XIAP and inhibit its ability to block caspase-activity. In addition, GPS2 induced caspase-mediated cell death in two different tumour cell lines and XIAP inhibited this effect.

    The second binding partner, Nulp1, preferentially bound XIAP in the presence of the apoptosis-inducer staurosporine. Nulp1 induced or sensitized cell lines to cell death when overexpressed, but this was not blocked by caspase-inhibitors or XIAP, suggesting a different reason for binding than apoptosis regulation. With the aim to understand the Nulp1-XIAP interaction, we continued to study Nulp1 in vivo and in vitro. We studied three different splice variants of Nulp1 and found that they were regulated by poly-ubiquitination and nuclear shuttling. Also, Nulp1 was expressed in embryonic mice, especially in the cortical plate, hippocampal neurons and cerebellar granular neurons. Expression of Nulp1 decreased with age but was still present in cerebellar deep nuclei and Purkinje cells of adult mice.

    To summarize, we have identified GPS2 as an apoptosis-inducing factor and an inhibitor of XIAP in vitro, and Nulp1 as a XIAP-interacting protein during staurosporine-induced apoptosis.

    List of papers
    1. G-protein pathway suppressor 2 protein induces cell death by activating caspase-3 and inhibits XIAP in vitro
    Open this publication in new window or tab >>G-protein pathway suppressor 2 protein induces cell death by activating caspase-3 and inhibits XIAP in vitro
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97221 (URN)
    Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-01-13Bibliographically approved
    2. Nuclear localized protein-1 (Nulp1) increases cel death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein
    Open this publication in new window or tab >>Nuclear localized protein-1 (Nulp1) increases cel death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein
    2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, ISSN 0006-291X, Vol. 366, no 2, p. 432-437Article in journal (Refereed) Published
    Abstract [en]

    Nuclear localized protein-1 (Nulp1) is a recently identified gene expressed in mouse and human tissues particularly during embryonic development. Nulp1 belongs to the family of basic helix-loop-helix (bHLH) proteins that are important in development. The precise function of Nulp1 in cells is however not known. We observed that overexpression of Nulp1 induces a large increase in cell death of human osteosarcoma Saos2 cells with DNA fragmentation. In mouse N2A neuroblastoma cells Nulp1 affected cell proliferation and sensitized cells towards death induced by staurosporine. Staining using a novel antibody localized Nulp1 mainly to the cell nucleus and to some extent to the cytoplasm. Nulp1 binds the X-linked inhibitor of apoptosis protein (XIAP) and this interaction was increased during cell death. These results indicate that Nulp1 plays a role in cell death control and may influence tumor growth.

    Keywords
    Nulp1, Cell death, XIAP, Tumor cells
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97222 (URN)10.1016/j.bbrc.2007.11.146 (DOI)000252436300026 ()18068114 (PubMedID)
    Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2017-12-14Bibliographically approved
    3. Nulp1/Tcf25 isoforms are differentially regulated through ubiquitination and subcellular localization in neuroblastoma cells
    Open this publication in new window or tab >>Nulp1/Tcf25 isoforms are differentially regulated through ubiquitination and subcellular localization in neuroblastoma cells
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97223 (URN)
    Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-01-13Bibliographically approved
    4. Nulp1 is expressed in developing mouse brain and in neuronal progenitor cells
    Open this publication in new window or tab >>Nulp1 is expressed in developing mouse brain and in neuronal progenitor cells
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97224 (URN)
    Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-01-13Bibliographically approved
  • 8.
    Steen, Håkan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Korhonen, Laura
    Hansson, Inga
    Lindholm, Dan
    Nulp1 is expressed in developing mouse brain and in neuronal progenitor cellsManuscript (Other academic)
  • 9.
    Steen, Håkan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Lindholm, Dan
    Nulp1/Tcf25 isoforms are differentially regulated through ubiquitination and subcellular localization in neuroblastoma cellsManuscript (Other academic)
  • 10.
    Wootz, Hanna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Amyotrophic Lateral Sclerosis – A Study in Transgenic Mice2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an incidence of 1.5-2.7/100000 people/year. Today there is no cure for the disease and only symptomatic treatments are available. ALS progresses rapidly and only 50% of the patients are alive three years after the symptom debut. In ALS, the upper and lower motor neurons undergo degeneration in a process resembling apoptosis. This leads to muscle atrophy and paralysis. The causes of neuronal death are however unknown. In this thesis we have studied transgenic mice carrying human mutant superoxide dismutase, as a model for familial ALS. These mice develop ALS-like symptoms after four months of age with degeneration of the motor neurons. Our results show an involvement of endoplasmic reticulum stress, caspase-12, -9, -3 and procaspase-7 in the ALS mice spinal cord. Overexpression of the antiapoptotic protein XIAP in spinal cord neurons inhibited the activation of caspase-12 and reduced caspase-3 and calpain activity. Calpastatin, the regulator of calpain activity, was kept intact in the ALS-XIAP mice. These mice showed a 12% increase in the mean survival suggesting a beneficial effect of XIAP in ALS. The reason for the ultimate cell death of motor neurons in the ALS-XIAP mice may be due to the activation of additional cell death pathways. Thus, we observed that lysosomal proteases particularly, cathepsinB, -D, and -L were activated in the ALS mice spinal cord together with a less marked upregulation of the inhibitors, cystatinB and -C. We also found activation of astrocytes and microglial cells in the spinal cord of ALS mice indicating their involvement in the disease. The results show that both caspase-dependent and -independent pathways are activated during neuronal degeneration in the ALS spinal cord. The results obtained may help to identify novel drug targets for future treatments of ALS.

    List of papers
    1. Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS
    Open this publication in new window or tab >>Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS
    Show others...
    2004 In: Biochemical and Biophysical Research Communications, ISSN 0006-291X, Vol. 322, no 1, p. 281-286Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95176 (URN)
    Available from: 2006-11-24 Created: 2006-11-24Bibliographically approved
    2. XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice
    Open this publication in new window or tab >>XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice
    2006 In: Experimental Cell Research, ISSN 0014-4827, Vol. 312, no 10, p. 1890-1898Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95177 (URN)
    Available from: 2006-11-24 Created: 2006-11-24Bibliographically approved
    3. Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: Possible roles in motor neuron survival
    Open this publication in new window or tab >>Altered distribution and levels of cathepsinD and cystatins in amyotrophic lateral sclerosis transgenic mice: Possible roles in motor neuron survival
    2006 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 143, no 2, p. 419-430Article in journal (Refereed) Published
    Abstract [en]

    In amyotrophic lateral sclerosis (ALS) there is a selective degeneration of motor neurons leading to muscle paralysis and death. The mechanism underlying cell demise in ALS is not fully understood, but involves the activation of different proteolytic enzymes, including the caspase family of cysteine proteases. We have here studied whether other proteases, such as the cathepsins, residing in lysosomes, and the cathepsin inhibitors, cystatinB and -C are changed in ALS. The expression and protein levels of the cathepsinB, -L and -D all increased in the spinal cord in ALS mice, carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. At the cellular level, cathepsinB and -L were present in ventral motor neurons in controls, but in the ALS mice cathepsinB was also expressed by glial fibrillary acidic protein (GFAP) positive astrocytes. The distribution of the aspartic protease, cathepsinD also changed in ALS with a loss of the lysosomal staining in motor neurons. Inhibition of caspases by means of X-chromosome-linked inhibitor of apoptosis protein (XIAP) overexpression did not inhibit cleavage of cathepsinD in ALS mice, suggesting a caspase-independent pathway. Expression of cystatinB and -C increased slightly in the ALS spinal cords. Immunostaining showed that in ALS, cystatinC was present in motor neurons and in GFAP positive astrocytes. CystatinB that is a neuroprotective factor decreased in motor neurons in ALS but was expressed by activated microglial cells. The observed changes in the levels and distributions of cathepsinD and cystatinB and-C indicate a role of these proteins in the degeneration of motor neurons in ALS.

    Keywords
    nerve cell death, cathepsinD, cystatinB, cystatinC, microglia, ALS
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-95178 (URN)10.1016/j.neuroscience.2006.07.048 (DOI)000242351100006 ()16973300 (PubMedID)
    Available from: 2006-11-24 Created: 2006-11-24 Last updated: 2017-12-14Bibliographically approved
  • 11.
    Wootz, Hanna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Hansson, Inga
    Korhonen, Laura
    Lindholm, Dan
    XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice2006In: Experimental Cell Research, ISSN 0014-4827, Vol. 312, no 10, p. 1890-1898Article in journal (Refereed)
  • 12.
    Wootz, Hanna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
    Hansson, Inga
    Korhonen, Laura
    Näpänkangas, Ulla
    Lindholm, Dan
    Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS2004In: Biochemical and Biophysical Research Communications, ISSN 0006-291X, Vol. 322, no 1, p. 281-286Article in journal (Refereed)
1 - 12 of 12
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