Modulation of nuclear receptor function by interacting proteins
Author: Osman, Waffa
Date: 2007-09-11
Location: Sal 6F, Alfred Nobels allé 8, Karolinska Institutet, Huddinge
Time: 09.00
Department: Biovetenskaper och näringslära / Biosciences and Nutrition
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thesis.pdf (1.103Mb)
Abstract
Nuclear receptors are a family of transcription factors involved in many
biological processes. They represent key potentials as therapeutic
targets for several clinical conditions such as diabetes, obesity,
cardiovascular disease and cancer, because their activity is modulated by
small molecules. Collectively these diseases represent a large market for
prescription drugs. The nuclear receptor family consists of 48 members.
The nuclear receptors have three conserved domains, the N-terminal
transactivation domain, the central DNA binding domain and the C-terminal
ligand binding domain. Nuclear receptors are ligand activated
transcription factors that are not only regulated by small lipophilic
ligands, but also by interaction with coactivators and corepressors as
well as other binding proteins. Protein-protein interactions are
essential in many biological pathways and are also attractive for drug
discovery. In this thesis I elucidate the functional significance of some
nuclear receptor interacting proteins. I have investigated the mechanism
of the corepressor receptor interacting protein 140 (RIP140) for
repression of glucocorticoid receptor (GR) and liver X receptor (LXR) and
the functional significance of the novel interacting proteins
polyamine-modulated factor 1 (PMF-1) and germinal center associated
nuclear protein (GANP) in glucocorticoid signalling.
RIP140 represses ligand activated nuclear receptors, such as GR and LXR.
It is localized in small nuclear foci targeted by a 40 amino acid long
sequence. Even though the foci targeting sequence in RIP140 overlaps with
the binding site of the corepressor C-terminal binding protein (CtBP),
interaction with CtBP is not essential for foci targeting. Upon
coexpression of ligand activated GR or LXR with RIP140 is redistributed
to larger foci distinct from RIP140 foci. The redistribution of RIP140/GR
involves RIP140 repression domains and the DNA binding domain of GR.
RIP140 repression domains include the C-terminal receptor interacting
LXXLL motifs binding to GR and the interaction domain of the corepressor
CtBP. The repression of RIP140/LXR involves the integrity of the
C-terminal domain of RIP140 including the LXXML motif. Jointly, these
results suggested that RIP140 represses in multiple ways including direct
binding to ligand activated NR and the formation and redistribution of
intranuclear repressive protein complexes.
PMF-1 is a transcription factor induced by polyamines, which are
important regulators of cell growth and cell death and are implicated in
glucocorticoid induced apoptosis. We identified PMF-1 to functionally
interact with RIP140 and GR. PMF-1 represses glucocorticoid induced GR
activity and has an intrinsic repression activity, which could contribute
to the repressive action. Although a physical interaction was observed
between PMF-1 and RIP140, we found that PMF-1 does not further enhance
RIP140 repressive effect.
We identified GANP and the GANP splice variant MCM3 associated protein
(MCM3AP) to bind to GR ligand binding domain. We found GANP to be a
shuttling protein that shuttles between the nucleus and the cytoplasm,
and contains nuclear localization and nuclear export signals. GANP and
MCM3AP were initially reported as proteins binding to MCM3, which is a
member of the MCM protein complex that is involved in initiating of DNA
replication. We show that glucocorticoids regulate the chromatin loading
of MCM3, inhibit DNA replication and arrest cells in the G1 phase of the
cell cycle. We also show that MCM3AP counteracts the repressive activity
of glucocorticoid on DNA replication. In conclusion we suggest that
interaction between GR, GANP/MCM3AP and MCM3 could imply a new way for
glucocorticoid regulation of cell proliferation.
List of papers:
I. Tazawa H, Osman W, Shoji Y, Treuter E, Gustafsson JA, Zilliacus J (2003). "Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140." Mol Cell Biol 23(12): 4187-98
Pubmed
II. Jakobsson T, Osman W, Gustafsson JA, Zilliacus J, Wärnmark A (2007). "Molecular basis for repression of liver X receptor-mediated gene transcription by receptor-interacting protein 140." Biochem J 405(1): 31-9
Pubmed
III. Shoji Y, Osman W, Zilliacus J (2007). "Polyamine-modulated factor 1 represses glucocorticoid receptor activity. " Biochem Biophys Res Commun 361(1): 176-81. Epub 2007 Jul 16
Pubmed
IV. Osman W, Laine S, Zilliacus J (2006). "Functional interaction between the glucocorticoid receptor and GANP/MCM3AP." Biochem Biophys Res Commun 348(4): 1239-44. Epub 2006 Aug 7
Pubmed
I. Tazawa H, Osman W, Shoji Y, Treuter E, Gustafsson JA, Zilliacus J (2003). "Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140." Mol Cell Biol 23(12): 4187-98
Pubmed
II. Jakobsson T, Osman W, Gustafsson JA, Zilliacus J, Wärnmark A (2007). "Molecular basis for repression of liver X receptor-mediated gene transcription by receptor-interacting protein 140." Biochem J 405(1): 31-9
Pubmed
III. Shoji Y, Osman W, Zilliacus J (2007). "Polyamine-modulated factor 1 represses glucocorticoid receptor activity. " Biochem Biophys Res Commun 361(1): 176-81. Epub 2007 Jul 16
Pubmed
IV. Osman W, Laine S, Zilliacus J (2006). "Functional interaction between the glucocorticoid receptor and GANP/MCM3AP." Biochem Biophys Res Commun 348(4): 1239-44. Epub 2006 Aug 7
Pubmed
Issue date: 2007-08-21
Rights:
Publication year: 2007
ISBN: 978-91-7357-264-4
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