ERA

Download the full-sized PDF of Understanding the function of the JunB transcription factor in anaplastic lymphoma kinase-positive, anaplastic large cell lymphomaDownload the full-sized PDF

Analytics

Share

Permanent link (DOI): https://doi.org/10.7939/R3N697

Download

Export to: EndNote  |  Zotero  |  Mendeley

Communities

This file is in the following communities:

Graduate Studies and Research, Faculty of

Collections

This file is in the following collections:

Theses and Dissertations

Understanding the function of the JunB transcription factor in anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma Open Access

Descriptions

Other title
Subject/Keyword
lymphoma
JunB
ALK+ ALCL
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Pearson, Joel Dylan
Supervisor and department
Ingham, Robert (Medical Microbiology and Immunology)
Examining committee member and department
Berthiaume, Luc (Cell Biology)
Barry, Michele (Medical Microbiology and Immunology)
Baldwin, Troy (Medical Microbiology and Immunology)
Harder Kenneth (Microbiology and Immunology, UBC)
Department
Department of Medical Microbiology and Immunology
Specialization
Immunology
Date accepted
2013-07-09T09:37:37Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is a non-Hodgkin lymphoma thought to arise from an activated T lymphocyte. This lymphoma is characterized by the presence of chromosomal translocations involving the ALK tyrosine kinase, which generate oncogenic fusion proteins, most commonly nucleophosmin (NPM)-ALK. NPM-ALK activates many signalling pathways that drive the proliferation, survival and migration of ALK+ ALCL cells. One of the downstream effectors of NPM-ALK signalling is the activator protein-1 family transcription factor, JunB. JunB is highly expressed in ALK+ ALCL and was reported to promote proliferation of ALK+ ALCL cell lines. Despite this, transcriptional targets of JunB that are important in the pathogenesis of ALK+ ALCL were largely uncharacterized. To better understand the function of JunB in ALK+ ALCL, we performed a quantitative mass spectrometry screen to identify JunB-regulated proteins in ALK+ ALCL cell lines. We identified the serine protease, Granzyme B (GzB), and the heat shock protein-90 co-chaperone, Cyclophilin 40 (Cyp40), as potential JunB-regulated proteins in ALK+ ALCL. Here, we demonstrate that GzB and Cyp40 are JunB transcriptional targets, and that NPM-ALK and JunB signalling promotes GzB and Cyp40 expression in ALK+ ALCL. By regulating the expression of GzB and the related protein, Perforin, we show that NPM-ALK and JunB influence the cytotoxic phenotype observed in ALK+ ALCL. Since the expression of GzB and Cyp40 was promoted by oncogenic signalling in ALK+ ALCL, we examined whether they play important roles in the pathogenesis of this lymphoma. Interestingly, we found that GzB expression actually sensitized ALK+ ALCL cell lines to apoptosis following treatment with apoptosis-inducing drugs. This finding is consistent with the observation that ALK+ ALCL patients are often successfully treated using standard chemotherapy regimens. We further found that Cyp40 promoted the viability of ALK+ ALCL cell lines. Together, our results shed light onto the function of an important transcription factor in ALK+ ALCL, and demonstrate that JunB regulates the expression of genes that contribute to multiple aspects of ALK+ ALCL biology. Furthermore, our findings uncover novel signalling events downstream of the NPM-ALK oncoprotein, and better clarify the molecular mechanisms underlying ALK+ ALCL phenotype and pathogenesis.
Language
English
DOI
doi:10.7939/R3N697
Rights
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 these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before 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.
Citation for previous publication
Pearson JD, Lee JKH, Bacani JTC, Lai R, and Ingham RJ. (2012) NPM-ALK: the prototypic member of a family of oncogenic tyrosine kinases. Journal of Signal Transduction. 2012:123253. (Review Article).Pearson JD, Lee JKH, Bacani JTC, Lai R, and Ingham RJ. (2011) NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma. International Journal of Clinical and Experimental Pathology. 4:124-133.Pearson JD, Mohammed Z, Bacani JTC, Lai R, and Ingham RJ. (2012) The heat shock protein-90 co-chaperone, Cyclophilin 40, promotes ALK-positive anaplastic large cell lymphoma and its regulation is regulated by the NPM-ALK oncoprotein. BMC Cancer. 12:229.

File Details

Date Uploaded
Date Modified
2014-04-24T23:15:04.800+00:00
Audit Status
Audits have not yet been run on this file.
Characterization
File format: pdf (Portable Document Format)
Mime type: application/pdf
File size: 6695619
Last modified: 2015:10:12 12:11:53-06:00
Filename: Pearson_Joel_Fall 2013.pdf
Original checksum: 23133d23fcbe5b92c7f0add7aa662f50
Well formed: true
Valid: true
File author: Joel
Page count: 258
File language: en-CA
Activity of users you follow
User Activity Date