The Dual Role of OCA-B in B Cell Development and Signaling

<p>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 BCR dependent 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 cDNA 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-B1 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-b-/- 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2006

Author dc:creator

• Siegel, Rachael

Contributors dc:contributor

• Robert G. Roeder

• B cell development
• OCA-B
• B cell receptor signaling
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/62

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1061