Tahiri, R;
(2013)
The role of Stanniocalcin-1 in vascular cell function.
Doctoral thesis (PhD), UCL (University College London).
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Abstract
Stanniocalcin-1 (STC-1) is a 56kDa disulphide-linked homodimeric glycoprotein in vertebrates, with the capacity to regulate the extracellular ionised calcium (Ca2+) concentration. Specifically, in fish, Stanniocalcin (STC) is released into bloodstream in response to rising serum calcium levels by acting on calcium sensitive receptors on both gill and intestine epithelial cells to reduce the calcium uptake. Initially, STC was identified as a secreted hormone having an inhibitory effect on whole body Ca2+ influx that prevents hypercalcemia. However the function of this protein in mammals is still unclear. During angiogenesis, essential angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-derived Growth Factor (PDGF), initiate cellular responses, intracellular signaling events that drive proliferation, migration and survival of vascular endothelial and smooth muscle cells (SMCs), respectively. Thus, it is important to understand the physiology of the molecular mechanism through which VEGF and/or PDGF exerts its biological activities as well as its role in malignancies in order to develop anti-angiogenic strategies for therapeutic intervention. In the first part of this thesis, the role of STC-1 in endothelial cell function was characteristed using varirous approaches. Analysis of VEGF-stimulated migration showed that STC-1 can modulate endothelial cell motility but has no effect on endothelial cell signalling. Here, I identified for the first time that PDGF-BB but not PDGF-AA, strongly upregulates expression of STC-1 in vascular smooth muscle cells. PDGF-BB-induced STC-1 expression is at least partially mediated via PDGFRα and possibly PDGFRα/β heterodimers, but there appears to be compensation between the two receptors. However, the partial inhibition of STC-1 expression by siRNA-mediated knockdown of both PDGFRs raises the possibility that an unconventional pathway is also involved not mediated by known PDGFRs, or by a non-Receptor Tyrosine Kinase (RTK) pathway. Furthermore, a novel synergistic effect of STC-1 and PDGF-BB in SMCs on phosphorylation of Akt/PBK protein that leads to GSK3 inhibition was observed. As a PDGF-induced protein, STC-1 is implicated in modulating PDGF-mediated cell motility, and is a potential modulator of PI3K-Akt pathway activation. Akt enhanced phosphorylation might indicate a role for STC-1 in regulating SMC survival.
Type: | Thesis (Doctoral) |
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Qualification: | PhD |
Title: | The role of Stanniocalcin-1 in vascular cell function |
Open access status: | An open access version is available from UCL Discovery |
Language: | English |
UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1398795 |
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