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Biological role of the tumor suppressor protein, RASSF1A in Inflammation and Cancer Open Access

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Other title
Subject/Keyword
RASSF1A
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
El-Kalla, Mohamed
Supervisor and department
Shairaz Baksh (Pediatrics)
Jason Dyck (Pediatrics)
Examining committee member and department
Hien Huynh (Pediatrics)
Karen Madsen (medicine)
Department
Medical Sciences-Pediatrics
Specialization

Date accepted
2010-01-07T17:34:57Z
Graduation date
2010-06
Degree
Master of Science
Degree level
Master's
Abstract
Inflammatory bowel disease (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic intestinal diseases characterized by inflammation of the gastrointestinal area resulting in abdominal pain, chronic diarrhoea, and weight loss. IBD affects 1 in 1000 individuals and between 10% and 15% of CD patients are children (with northern Alberta having one of the highest rates of CD in the world). Molecularly, it is characterized by hyperactivation of the transcription factor, nuclear factor κ B (NFκB), and elevated production of pro-inflammatory cytokines. RASSF1A is a tumor suppressor protein required for death receptor dependent cell death (apoptosis) originating from the tumor necrosis factor alpha (TNFα) receptor (TNF-R1). It is one of the most methylated genes identified in human cancers and one of the earliest detectable loss in cancer. Loss of RASSF1A expression arises by methylation of the promoter for exon 1Aα (encoding the N-terminal 119 amino acids) without epigenetic loss of the other isoforms of RASSF1, suggesting selective pressure to silence isoform RASSF1A. We have defined apoptotic regulation by RASSF1A involving death receptors (such as TNF-R1) and its downstream target modulator of apoptosis, MOAP-1. We now define a novel role for RASSF1A in modulating innate immunity. Rassf1a-/- mice rapidly become sick following challenge with LPS or dextran sulphate in comparison to wild type animals and cytokine analysis of the peripheral blood reveal an elevated production of NFκB regulated cytokines (IL-6, IL-12, IL-8 and IL-10) Rassf1a-/- mice when compared to wild type animals. We propose that RASSF1A is an emerging novel negative regulator of inflammation and maybe a new susceptibility gene for inflammatory diseases.
Language
English
DOI
doi:10.7939/R3TX3R
Rights
License granted by Mohamed El-Kalla (elkalla@ualberta.ca) on 2010-01-04T23:49:18Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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