Abstract/Details

B-cell lymphoma gene 6: Insights into mechanisms of functional regulation


2009 2009

Other formats: Order a copy

Abstract (summary)

BCL6 is a sequence specific transcription repressor required for germinal center (GC) formation. In normal B cells, BCL6 exerts its regulatory role through repression of genes associated with B cell activation, response to DNA damage, cell-cycle regulation and plasma cell differentiation. Deregulated expression of BCL6 is found in many GC-derived Diffuse Large B cell Lymphomas (DLBCLs). Mouse models engineered to recapitulate BCL6 deregulation in DLBCL have confirmed a causative role for BCL6 in the pathogenesis of these tumors. This study examines BCL6 protein functional modulation caused by its interacting partners, post-translational modification and inactivating mutations. First, resulting from the identification of the HAT protein Tip60 as a BCL6 interacting partner, we examined Tip60-dependent acetylation of BCL6. Ultimately no evidence for this was obtained, however our results suggest a potential role for Tip60 in BCL6 protein stabilization in a HAT-independent manner in Type III DLBCLs. Next we studied BCL6 post-translational modification by the small ubiquitin-like modifier, SUMO. BCL6 contains a number of putative sumoylation sites. Using in vitro and in vivo sumoylation assays, we were able to demonstrate that BCL6 can, in fact, be sumoylated and that BCL6 sumoylation appears to involve multiple substrate lysine sites. Our last study centered on the identification of novel BCL6 coding region mutations. Lymphoma-associated BCL6 deregulation is believed to occur only at the transcriptional level so that lymphoma B cells still express a wild type BCL6 protein. Here we report the identification and characterization of a novel coding region mutation in the zinc finger domain of BCL6 in a DLBCL cell line. The mutation, C579R, disrupts a cysteine residue required for the structural integrity of the third ZF leading to compromised DNA binding and therefore impaired transcriptional repression capacity. In vivo growth/survival assays demonstrate that B cells over-expressing this mutant have an advantage over their WT expressing counterparts. Our data suggest a tumor suppressive activity of BCL6 which can be targeted by spontaneous mutation during lymphomagenesis. In support of this, we also report in this study, the identification of BCL6 mutations in additional DLBCL cell lines and in primary samples from DLBCL patients.

Indexing (details)


Subject
Cellular biology;
Immunology
Classification
0379: Cellular biology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Biological sciences; B cell lymphomas; DNA damage; Germinal centers
Title
B-cell lymphoma gene 6: Insights into mechanisms of functional regulation
Author
Krupski-Downs, Melissa A.
Number of pages
209
Publication year
2009
Degree date
2009
School code
0266
Source
DAI-B 70/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109398854
Advisor
Ye, B. Hilda
University/institution
Yeshiva University
University location
United States -- New York
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3380851
ProQuest document ID
305041179
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305041179
Access the complete full text

You can get the full text of this document if it is part of your institution's ProQuest subscription.

Try one of the following:

  • Connect to ProQuest through your library network and search for the document from there.
  • Request the document from your library.
  • Go to the ProQuest login page and enter a ProQuest or My Research username / password.