Student Theses and Dissertations

Date of Award

2006

Document Type

Thesis

RU Laboratory

Roeder Laboratory

Keywords

B cell development, OCA-B, B cell receptor signaling

Abstract

OCA-B (Oct coactivator from B cells) is a B-cell specific coactivator of transcription that acts in conjunction with the ubiquitously expressed activator, OCT-1 or the B cell-restricted OCT-2. OCT-1 or OCT-2 can bind an upstream octamer element with the consensus sequence 5'- ATGCAAAT-3' in target gene promoters and enhancers. At the octamer element, the OCT-1/2-OCA-B complex is able to regulate gene expression via interaction with the basal transcription machinery. OCA-B was originally identified as a nuclear transcriptional coactivator and then shown to be essential for antigen-driven immune responses, including secondary isotype expression, germinal center formation and BCRdependent proliferation. These defects contribute to the severely impaired antigen-dependent immune responses of Oca-b^- mice. The later identification of a membrane-bound, myristoylated form of OCA-B suggested additional, potentially unique functions in B cell signaling pathways and that OCA-B might function through both transcriptional and non-transcriptional mechanisms within the cell. Therefore, a strong focus was placed on identifying additional OCA-B target genes that could explain its role in the antigen-dependent immune response. Importantly, this study has identified, by c D N A microarray, several genes that fail to be up regulated in the Oca-b^- activated B cells. OCA-B deficient cells have a compromised response to BCR signaling and many of the identified OCA-B target genes (e.g. Kcnn4, Lck, CyclinD3, and Cdc37) play important roles in cell signaling; however, their specific functions in B cell development and activation are largely unknown. From multiple primary B cell stages, we have found that key OCA-B target genes are expressed and regulated throughout B cell development. This study has identified a novel developmental block in Oca-b^- mice, which indicates that OCA-B also functions in the pre-Bl to pre-B2 cell transition by mediating pre-BCR signaling. Most surprisingly, OCA-B directly interacts with SYK, a tyrosine kinase critical for pre-BCR and BCR signaling. This unprecedented type of interaction — of a transcriptional coactivator with a signaling kinase — takes place in the cytoplasm and directly regulates SYK stability. Combined with the deregulation of OCA-B target genes, this may help explain both previously observed defects in the antigen-dependent immune response of Oca-fr/- mice and newly identified defects in early B cell development. This study indicates that OCA-B is required for a complete response to pre-BCR and BCR signaling at multiple stages of B cell development, through its non-transcriptional regulation of SYK.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/236

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