Investigating the role of the post-transcriptional regulator protein ZFP36L1 in B-cell functions

ZFP36L1 belongs to a class of RNA-binding proteins known as the ZFP36 protein family which consist of three other members namely ZFP36, ZFP36L2 and ZFP36L3. All the members of the ZFP36 protein family have been reported to bind to the ARE in the 3’ UTR regions of the target mRNA (via the zinc finger domains) and subsequently result in the destabilization and degradation of the mRNA. Established targets of ZFP36L1 include TNF-a, GM-CSF, VEGF, IL-3, C-IAP2, NOTCH 1, STAR, STATSb and DIM. The knowledge about the function of ZFP36L1 and its role in post-transcriptional regulation in B-cell development is extremely limited. The primary aim of this project was to investigate role of ZFP36L1 in regulating B-cell development, in particular late B-cell development (plasma-cell differentiation). BCL-1 cells (provide a model system to study plasma-cell differentiation) were found to express relatively high levels of ZFP36L1 and the cytokine-induced plasmacytic differentiation was associated with downregulation of ZFP36L1 expression. In order to determine a direct involvement of a downregulation of ZFP36L1 expression in plasmacytic differentiation process, lentiviruses expressing shRNAs targeting the zfp3611 mRNA were employed to downregulate ZFP36L1 expression in BCL-1 cells. Efficient downregulation of zfp3611 mRNA expression and ZFP36L1 protein expression was established in unstimulated BCL1 .zfp3611 .RNAi cells. It was observed that BCL1 .zfp3611 .RNAi cells produced higher amounts of IgM compared with control cells. This result suggested that a downregulation of ZFP36L1 expression in BCL-1 cells results in an increase in IgM production (a phenotype associated with BCL-1 cells undergoing plasmacytic differentiation). The results seem to be consistent with other studies suggesting a role of ZFP36L1 in negatively regulating differentiation, although this would need to be investigated further.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2012

Author dc:creator

• Nasir, Asghar

Advisors dc:contributor.advisor

• Murphy, John
• Thompson, Stephen

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/ba5f7f24-34bd-4e67-9800-90ec51c57a9b

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/ba5f7f24-34bd-4e67-9800-90ec51c57a9b