Persistent Link:
http://hdl.handle.net/10150/194846
Title:
PRL Phosphatases: Expression and Function in Pancreatic Cancer
Author:
Stephens, Bret
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
One of the current goals in cancer research is to discover and validate novel molecular targets that may be useful for diagnostic and therapeutic purposes in fighting this disease. The PRL phosphatases (PRL-1, PRL-2, and PRL-3) are low molecular weight protein tyrosine phosphatases with unknown biological function(s) that have gained attention from cancer researchers in the past couple of years, mainly due to reports that these phosphatases may play important roles in tumor progression and metastasis. Motivated by the particular urgent need for molecular targets in pancreatic cancer this work was undertaken to determine what role PRL proteins played in pancreatic cancer biology and to determine if targeting PRLs would be effective in treating this disease. In this dissertation, it was found that both PRL-1 and PRL-2, but not PRL-3 are upregulated in pancreatic adenocarcinomas, suggesting that some cancer cells are dependent upon their activity for continued proliferation and survival. To validate this hypothesis, siRNAs were used in cell-based assays to evaluate the biological consequences of PRL-1 and/or PRL-2 inhibition. It was found that perturbations in PRL phosphatase signaling result in reduced proliferation, migration and especially the ability to grow in soft agar. Oligonucleotide microarray analysis revealed that many Erk and/or Akt dependent stress and growth factor inducible genes were differentially regulated between pancreatic cancer cells treated with PRL-targeting siRNA and their non-targeting siRNA treated counterparts. Subsequently, PRL knockdown was found to alter serum induced as well as amino acid deprivation induced Akt and Erk phosphorylation in multiple pancreatic cancer cell lines, suggesting that PRLs function upstream of these key pathways. Interestingly, we show that PRL proteins in cell free assays exhibit higher activity on doubly phosphorylated phosphatidylinositol substrates than tyrosine-phosphorylated peptides, suggesting that the biological substrate(s) might include non-protein molecules. These data support the hypothesis that PRL-1 and PRL-2 might play important biological roles in pancreatic cancer cells and further studies should be undertaken to determine the usefulness of these phosphatases as potential molecular biomarkers and targets.
Type:
text; Electronic Dissertation
Keywords:
PRL-1; PRL-2; phosphatases; pancreatic cancer
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Molecular & Cellular Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Mount, David
Committee Chair:
Mount, David

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titlePRL Phosphatases: Expression and Function in Pancreatic Canceren_US
dc.creatorStephens, Breten_US
dc.contributor.authorStephens, Breten_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractOne of the current goals in cancer research is to discover and validate novel molecular targets that may be useful for diagnostic and therapeutic purposes in fighting this disease. The PRL phosphatases (PRL-1, PRL-2, and PRL-3) are low molecular weight protein tyrosine phosphatases with unknown biological function(s) that have gained attention from cancer researchers in the past couple of years, mainly due to reports that these phosphatases may play important roles in tumor progression and metastasis. Motivated by the particular urgent need for molecular targets in pancreatic cancer this work was undertaken to determine what role PRL proteins played in pancreatic cancer biology and to determine if targeting PRLs would be effective in treating this disease. In this dissertation, it was found that both PRL-1 and PRL-2, but not PRL-3 are upregulated in pancreatic adenocarcinomas, suggesting that some cancer cells are dependent upon their activity for continued proliferation and survival. To validate this hypothesis, siRNAs were used in cell-based assays to evaluate the biological consequences of PRL-1 and/or PRL-2 inhibition. It was found that perturbations in PRL phosphatase signaling result in reduced proliferation, migration and especially the ability to grow in soft agar. Oligonucleotide microarray analysis revealed that many Erk and/or Akt dependent stress and growth factor inducible genes were differentially regulated between pancreatic cancer cells treated with PRL-targeting siRNA and their non-targeting siRNA treated counterparts. Subsequently, PRL knockdown was found to alter serum induced as well as amino acid deprivation induced Akt and Erk phosphorylation in multiple pancreatic cancer cell lines, suggesting that PRLs function upstream of these key pathways. Interestingly, we show that PRL proteins in cell free assays exhibit higher activity on doubly phosphorylated phosphatidylinositol substrates than tyrosine-phosphorylated peptides, suggesting that the biological substrate(s) might include non-protein molecules. These data support the hypothesis that PRL-1 and PRL-2 might play important biological roles in pancreatic cancer cells and further studies should be undertaken to determine the usefulness of these phosphatases as potential molecular biomarkers and targets.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectPRL-1en_US
dc.subjectPRL-2en_US
dc.subjectphosphatasesen_US
dc.subjectpancreatic canceren_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMount, Daviden_US
dc.contributor.chairMount, Daviden_US
dc.contributor.committeememberVon Hoff, Daniel D.en_US
dc.contributor.committeememberParker, Royen_US
dc.identifier.proquest2552en_US
dc.identifier.oclc659749585en_US
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