Transcriptional mechanisms directing terminal differentiation of B lineage cells
Author: Linderson, Ylva
Date: 2002-11-22
Location: Konferensrum A303, Mikrobilogiskt och Tumörbiologiskt Centrum, Karolinska Institutet, Nobels väg 16
Time: 9.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
The interaction between the B cell receptor (surface immunoglobulin) and
its ligand (antigen) can result in extensive cell growth and induction of
differentiation. The terminally differentiated B cell fulfills the
ultimate purpose of B cell existence: to secret antibodies in order to
protect the organism against invading pathogens.
A feature inherent to the immune system is the ability to discriminate
between structures that are perceived as foreign and structures that are
not. Since the B cell does not possess the necessary attributes to
evaluate the pathogenic status of the substrate, it is dependent on
additional external signals, often provided by helper T cells, to ensure
responses that are of benefit to the organism. Appropriately, these
supplementary signals are subsequently interpreted at the genetic level
by transcription factors to either implement, or prohibit, the preset
program of cellular differentiation.
Through genetic gain, and loss of function studies in rodents,
transcription factors critical for the development of B lineage cells
have been identified. Some of these factors, Pax5, PU. 1, NF-kappaB and
Oct-2, are instrumental in the work presented in this thesis.
The immunoglobulin heavy chain 3 enhancer (HS1,2) that is regulated by
these factors, was appended to a heterologous reporter gene and used as a
model to investigate transcriptional suppression and activation. The
first part of this thesis shows that NF-kappaB together with additional
activators is an important regulator of HS1,2 function. In subsequent
studies the transcriptional corepressor Groucho related gene 4 (Grg4) was
found to play a regulatory role in modulating the function of Pax5, PU.1
and Oct-2. Further characterization and identification of likely
molecular prerequisites led to the postulation of a co-recruitment model
for Grg4-mediated repression.
My observations suggested a possible explanation as to how a limited set
of transcription factors can serve as interpreters of signals that not
only initiate terminal B cell differentiation but can also inhibit its
developmental program.
List of papers:
I. Linderson Y, Cross D, Neurath MF, Pettersson S (1997). "NFE, a new transcriptional activator that facilitates p50 and c-Rel-dependent IgH 3 enhancer activity. " Eur J Immunol 27(2): 468-75
Pubmed
II. Linderson Y, French NS, Neurath MF, Pettersson S (2001). "Context-dependent Pax-5 repression of a PU.1/NF-kappaB regulated reporter gene in B lineage cells. " Gene 262(1-2): 107-14
Pubmed
III. Lindreson Y, Eberhard D, Malin SG, Johansson A, Busslinger M, Pettersson S (2002). "Co-recruitment of Grg4 to PU.1 is critical for Pax5 mediated repression of B cell specific genes." (Manuscript)
IV. Malin SG, Linderson Y, Almqvist J, Ernberg I, Pettersson S (2002). "Conformation dependent and Oct2 specific recruitment of the co-repressor Grg4." (Manuscript)
I. Linderson Y, Cross D, Neurath MF, Pettersson S (1997). "NFE, a new transcriptional activator that facilitates p50 and c-Rel-dependent IgH 3 enhancer activity. " Eur J Immunol 27(2): 468-75
Pubmed
II. Linderson Y, French NS, Neurath MF, Pettersson S (2001). "Context-dependent Pax-5 repression of a PU.1/NF-kappaB regulated reporter gene in B lineage cells. " Gene 262(1-2): 107-14
Pubmed
III. Lindreson Y, Eberhard D, Malin SG, Johansson A, Busslinger M, Pettersson S (2002). "Co-recruitment of Grg4 to PU.1 is critical for Pax5 mediated repression of B cell specific genes." (Manuscript)
IV. Malin SG, Linderson Y, Almqvist J, Ernberg I, Pettersson S (2002). "Conformation dependent and Oct2 specific recruitment of the co-repressor Grg4." (Manuscript)
Issue date: 2002-11-01
Publication year: 2002
ISBN: 91-7349-429-1
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