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The roles of inner nuclear membrane proteins during interphase and mitosis
Stockholm University, Faculty of Science, Department of Neurochemistry.
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

The nuclear envelope (NE) consists of two concentric membranes, the outer nuclear membrane (ONM) and the inner nuclear membrane (INM). The LINC (linker of nucleoskeleton and cytoskeleton) complex spans both the ONM and the INM connecting the cytoskeleton to the nucleoskeleton and chromatin. Only a few of the known INM proteins have been functionally characterized and shown to have important roles in chromatin organisation. Defects in the genes coding for proteins in the INM and the nuclear lamina give rise to serious human diseases, called envelopathies.

In 2009 (Buch et al. 2009) our group made two major discoveries. We showed for the first time, that an integral INM protein distributed along the microtubules of the mitotic spindle. This protein was therefore named Samp1, Spindle Associated Membrane Protein 1. The second discovery was that depletion of Samp1 caused detachment of the centrosome from the NE, suggesting that Samp1 is associated with the microtubule cytoskeleton both in interphase and mitosis.

In this thesis we continued to investigate Samp1´s role during interphase. We also wanted to investigate the localisation of Samp1 in the mitotic spindle and possible function during mitosis. We show that the expression of Samp1 mutants and depletion of Samp1 affects the distribution and organisation of A-type lamins, the LINC complex protein Sun1 and the LINC complex associated protein emerin. Thus, in interphase Samp1 is functionally connected to the LINC complex and the A-type lamina network. The LINC complex can help explain how the centrosomes detach from the NE in Samp1 depleted cells. In mitotic cells, we found that depletion of Samp1 caused prolonged metaphase and aberrant mitotic phenotypes such as bi-nucleation, enlarged nuclei and micronuclei. We also showed that Samp1 interacts with RanGTPase and importin-β, which are key players in assembling the mitotic spindle. Samp1 also modulates the levels of importin-β and NuMA in the mitotic spindle, which could explain the mitotic phenotypes that we se in Samp1 depleted cells. Here we present evidence showing, for the first time, that an INM protein is present on kinetochore microtubules and have an essential role for correct chromosome segregation and spindle assembly.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University , 2014. , 50 p.
Keyword [en]
Samp1, mitotic spindle, centrosome, LINC complex, Lamina, Sun1, mitosis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-102827ISBN: 978-91-7447-910-2 (print)OAI: oai:DiVA.org:su-102827DiVA: diva2:713325
Presentation
2014-05-13, Heilbronnsalen, C 458, Svante Arrheniusv. 16 B, Stockholm, 12:15 (English)
Opponent
Supervisors
Available from: 2014-04-25 Created: 2014-04-22 Last updated: 2015-03-05Bibliographically approved
List of papers
1. Samp1 is functionally associated with the LINC complex and A-type lamina networks
Open this publication in new window or tab >>Samp1 is functionally associated with the LINC complex and A-type lamina networks
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2011 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, 2077-2085 p.Article in journal (Refereed) Published
Abstract [en]

The transmembrane inner nuclear membrane (INM) protein Samp1 is required for anchoring centrosomes near the nuclei. Using high-resolution fluorescence microscopy we show that Samp1 is distributed in a distinct and characteristic pattern in the nuclear envelope (NE), where it partially colocalizes with the LINC complex protein Sun1. By studying the localization of Samp1 deletion mutants and fusion proteins, we conclude that the cysteine-rich N-terminal half of Samp1 is nucleoplasmically exposed and is responsible for targeting to the INM. It contains four conserved CxxC motifs with the potential to form zinc fingers. The distribution of cysteine-to-alanine substitution mutants, designed to prevent zinc finger formation, showed that NE localization of Samp1 depends on intact CxxC motifs. Overexpression of Samp1 zinc finger mutants produced an abnormal dominant phenotype characterized by disrupted organization of a selective subset NE proteins, including emerin, Sun1, endogenous Samp1 and, in some cases, lamin A/C, but not lamin B, Sun2 or nucleoporins. Silencing of Samp1 expression showed that emerin depends on Samp1 for its correct localization in the NE. Our results demonstrate that Samp1 is functionally associated with the LINC complex protein Sun1 and proteins of the A-type lamina network.

Keyword
Cancer, Centrosome, Laminopathies, Nuclear membrane, Nuclear migration
National Category
Biological Sciences Chemical Sciences
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-63558 (URN)10.1242/jcs.078923 (DOI)000291048000014 ()
Available from: 2011-10-23 Created: 2011-10-23 Last updated: 2017-12-08Bibliographically approved
2. The integral nuclear membrane protein Samp1 is essential for the mitotic process by modulating the levels of importin-β and NuMA in the mitotic spindle
Open this publication in new window or tab >>The integral nuclear membrane protein Samp1 is essential for the mitotic process by modulating the levels of importin-β and NuMA in the mitotic spindle
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
Samp1, mitotic spindle, centrosome, LINC complex, Lamina, Sun1, mitosis
National Category
Biological Sciences Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-102825 (URN)
Funder
Swedish Research Council, 621-2010-448Swedish Cancer Society, 110590
Available from: 2014-04-22 Created: 2014-04-22 Last updated: 2016-01-29Bibliographically approved

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