مجال
التميز
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تميز دراسي وبحثي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Lymphomas driven by Epstein–Barr virus
nuclear antigen-1 (EBNA1) are dependant upon Mdm2
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رابط إلى البحث:
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Click Here
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تاريخ النشر:
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25 April
2018
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موجز عن البحث:
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Epstein–Barr
virus (EBV)-associated Burkitt’s lymphoma is characterised by the
deregulation of c-Myc expression and a restricted viral gene expression
pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein
to be consistently expressed. EBNA1 is required for viral genome propagation
and segregation during latency. However, it has been much debated whether the
protein plays a role in viral-associated tumourigenesis. We show that the
lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to
EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to
this process. Tumour cell survival is supported by IL-2 and there is a skew
towards CD8-positive T cells in the tumour environment, while the immune
check-point protein PD-L1 is upregulated in the tumours. Additionally,
several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with
increased phosphorylation at ser166, an expression pattern not seen in
Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1
are upregulated in the tumours. Using four independent inhibitors of Mdm2 we
demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for
survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied
by upregulation of p53, instead cell death is linked to loss of E2F1
expression, providing new insight into the underlying tumourigenic mechanism.
This opens a new path to combat EBV-associated disease.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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EICC Annual
Conference 2017
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تاريخ الإنعقاد:
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3-6 April
2017
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مكان
الإنعقاد:
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Edinburgh,
United Kingdom
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طبيعة المشاركة:
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Poster Presentation
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عنوان المشاركة:
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Epstein-Barr Virus nuclear antigen-1,
action and reaction as an oncogene
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ملخص المشاركة:
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The
herpesvirus Epstein-Barr virus (EBV) leads to a life-long persistent
infection and greater than 90% of the adult population of the world are
seropositive. EBV is the causative agent of infectious mononucleosis, but in
addition, the virus is associated with certain tumours of B-cell and
epithelia cell origin (as well as some rare T- cell tumours). EBV nuclear
antigen 1 (EBNA1) is an essential viral protein, required for the
maintenance, replication and mitotic segregation of viral genome episomes.
EBNA1 is a DNA binding protein and also interacts with several cellular
proteins, thereby affecting host cell-signalling pathways and in so doing may
contribute to cell survival and proliferation. EBNA1 is the only latent
protein that is expressed in all EBV- associated malignancies and is thought
to play a significant role in viral tumourigenesis. In order to explore the
oncogenic mechanism of EBNA1, B-cell lymphoma samples from transgenic mice
expressing EBNA1 (EμEBNA1 mice) and/or c-Myc (Eμc-Myc mice) were analysed by
immunoblotting. Several candidate cellular proteins likely involved in the
tumourigenic process were examined, including Cmyc,
Mdm2,
p53, PTEN, Akt and others.
Overexpression
of specific MDM2 isoforms were detected in all EBNA1 tumour samples, not
detected c-Myc tumour samples, or in pre-tumour or transgene negative
samples. Thus there is a specific correlation of the overexpression of Mdm2,
with EBNA1- induced tumourigenesis, likely reflecting the underlying
mechanism. In addition, C-Myc was overexpressed in EBNA1 tumours, supporting
our previous observations regarding the cooperation of these two proteins in
tumourigenesis.
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المؤتمر (2):
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عنوان المؤتمر:
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European EBV Meeting
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تاريخ الإنعقاد:
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06-07 July 2017
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مكان
الإنعقاد:
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Berlin, Germany
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طبيعة المشاركة:
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Oral Presentation
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عنوان المشاركة:
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Epstein-Barr Virus Nuclear Antigen-1,
Action and Reaction as an Oncogene
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ملخص المشاركة:
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The
herpesvirus Epstein-Barr virus (EBV) leads to a life-long persistent
infection and greater than 90% of the adult population of the world are
seropositive. EBV is the causative agent of infectious mononucleosis, but in
addition, the virus is associated with certain tumours of B-cell and
epithelia cell origin (as well as some rare T-cell tumours). EBV nuclear
antigen 1 (EBNA1) is an essential viral protein, required for the
maintenance, replication and mitotic segregation of viral genome episomes.
EBNA1 is a DNA binding protein and also interacts with several cellular
proteins, thereby affecting host cell-signalling pathways and in so doing may
contribute to cell survival and proliferation. EBNA1 is the only latent
protein that is expressed in all EBV-associated malignancies and is thought
to play a significant role in viral tumourigenesis. In order to explore the
oncogenic mechanism of EBNA1, B-cell lymphoma samples from transgenic mice
expressing EBNA1 (EµEBNA1 mice) and/or c-Myc (Eµc-Myc mice) were analysed by
immunoblotting. Several candidate cellular proteins likely involved in the
tumourigenic process were examined, including C-myc, Mdm2, p53, PTEN, Akt and
others. Overexpression of specific MDM2 isoforms were detected in all EBNA1
tumour samples, not detected in c-Myc tumour samples, or in pre-tumour or
transgene negative samples. Thus there is a specific correlation of the
overexpression of Mdm2, with EBNA1-induced tumourigenesis, likely reflecting
the underlying mechanism. In addition, C-Myc was overexpressed in EBNA1
tumours, supporting our previous observations regarding the cooperation of
these two proteins in tumourigenesis.
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