Alkhedaiade, Adel Qlayel Hamdan
Studies of αvβ integrin functions in human B cell precursors.
PhD thesis, University of Glasgow.
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The αVβ5 integrin is a member of integrin family that binds to different ligands such as vitronectin, fibronectin and soluble CD23 in order to mediate different biological responses such as cell growth, adhesion and metastasis. It is expressed by B cell precursors and by different acute lymphocytic leukaemia cell lines such as SMS-SB cells. This thesis is an attempt to explain how the sCD23- αVβ5 integrin interaction stimulates SMS-SB cell growth and to study the role of the αVβ5 integrin and other receptors such as PDGF receptor and CXCR4 in B cell development in the bone marrow. The maturation and differentiation of B-cells occur due to several factors that impact on gene expression in its development program. This program is divided into two main phases, the antigen-independent B-cell development phase and antigen-dependent B-cell development phase, respectively. The antigen - independent phase of B cell development starts from the pluripotent haemopoietic stem cell (PHSC) and progresses through several successive stages which are identified by somatic recombination and rearrangement of both heavy and light chain genes.
Soluble CD23 and LP (a synthetic peptide derived from soluble CD23) significantly stimulate SMS-SB growth while a smaller growth stimulation is caused by either SDF1-α or PDGFAB. There are different signalling targets involved in the αVβ5 integrin-mediated proliferation due to its binding to either sCD23 or LP. These ligands enhance the association between the αVβ5 integrin and the PDGF receptor which promote the phosphorylation of both Jak2 and STAT5. Moreover, cell growth was reduced and the phosphorylation of Jak2 and STAT5 was also knocked down with using either PDGF receptor inhibitor (AG1295) or Jak2 inhibitor (AG490).
Both soluble CD23 and LP activate the STAT5-DNA binding and strongly increase its transcriptional activity. In addition, both ligands induce the phosphorylation of other different substrates such as STAT2, c-Src, c-yes and AMPKα2 which might be related to cell growth stimulation.
The αVβ5 integrin ligands also promote the phosphorylation of ERK1/2, p90RSK and activate a SRF transfected reporter gene. However, ERK1/2 and p90RSK phosphorylation was completely blocked by the specific MEK inhibitor (U0126). In similar context, SDF1-α stimulates the transcriptional activity of SRF but not STAT5 while PDGFAB does the opposite. Finally, soluble CD23 induces the proliferation of 697 and BAF03 which are other pre-B cell line models.
These data suggest that the αVβ5 integrin-ligated ligands stimulate SMS-SB cell growth by promoting different signalling pathways, mainly Jak2/STAT5 and MEK/ERK1/2 pathway.
Further work is required to determine the role of STAT5, p90RSK, c-Src and SRF in stimulating either the proliferation or apoptosis that promoted by the αVβ5 integrin-sCD23 interaction and to investigate the relationship between the activation of these targets.
||Alpha v Beta 5 Integrin, CD23, ALL, STAT5, Jak2, Erk1/2, p90RSK, SRF, SDF1, PDGF, PDGF receptor
||R Medicine > RZ Other systems of medicine
||College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
||Cushley, Prof. William
|Date of Award:
Mr Adel Alkhedaide
||Copyright of this thesis is held by the author.
||02 Dec 2011
||10 Dec 2012 14:03
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