| dc.contributor.author | Tan, Ernest Yoh. | en_US |
| dc.date.accessioned | 2014-10-21T12:35:23Z | |
| dc.date.available | 2005 | |
| dc.date.issued | 2005 | en_US |
| dc.identifier.other | AAINR08419 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/54751 | |
| dc.description | Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional cell-surface protein that is aberrantly expressed in many cancers and plays a key role in tumorigenesis and metastasis. Its diverse cellular roles include modulation of chemokine activity by cleaving dipeptides from the chemokine N-terminus, regulation of extracellular nucleoside metabolism by binding the ecto-enzyme adenosine deaminase (ADA), and interaction with the extracellular matrix by binding fibronectin and collagens. | en_US |
| dc.description | The objective of this thesis was to determine whether adenosine, a purine nucleoside that is present at increased levels in the hypoxic tumor microenvironment, might affect the expression of functional DPPIV at the surface of human colorectal carcinoma cells. Adenosine persistently reduced DPPIV protein expression at the surface of HT-29 cells. This down-regulation of DPPIV occurred at adenosine concentrations comparable to those present within the extracellular fluid of colorectal tumors growing in vivo, and was not elicited by inosine or guanosine. Neither cellular uptake of adenosine nor its phosphorylation was necessary for the down-regulation of DPPIV. | en_US |
| dc.description | The adenosine down-regulation of DPPIV from the surface of HT-29 cells occurred independently of classical adenosine receptor subtypes (A1, A2A, A2B, and A3), and was instead mediated by a novel cell-surface mechanism that induced an increase in protein tyrosine phosphatase (PTP) activity. This increase in PTP activity decreased the tyrosine phosphorylation of ERK1/2 MAP kinase that, in turn, was linked to the decline in DPPIV. The down-regulation of DPPIV occurred independently of changes in the activities of protein kinases A or C, PI3K, other serine/threonine phosphatases, or the p38 or JNK MAP kinases. | en_US |
| dc.description | The down-regulation of DPPIV protein at the cell surface was paralleled by decreases in DPPIV enzyme activity, binding of ADA, and the ability of cells to bind to extracellular matrix proteins. Adenosine, at concentrations that exist within solid tumors, therefore acts at the surface of colorectal carcinoma cells through a PTP-dependent mechanism to decrease the levels and functional activities of DPPIV. This down-regulation of DPPIV may increase the sensitivity of cancer cells to the tumor-promoting effects of adenosine and their response to chemokines and the extracellular matrix, facilitating their expansion and metastasis. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2005. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.title | Adenosine regulation of dipeptidyl peptidase IV expression and function in human colorectal carcinoma cells. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
