Βeta-Arrestin1 and G Protein-Coupled Receptor Kinase5 Regulate Cancer Progression

Hdl Handle:
http://hdl.handle.net/10675.2/317390
Title:
Βeta-Arrestin1 and G Protein-Coupled Receptor Kinase5 Regulate Cancer Progression
Authors:
Kim, Jae II ( 0000-0003-1668-3910 )
Abstract:
Cancer is a leading cause of death worldwide, accounting for nearly seven million deaths per year. Available clinical data establish a protective effect of COX-2 inhibition on human cancer progression, but the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer therapeutics. Major COX-2 effectors are prostaglandins and we explored the idea that PGE2 promotes mitogenic signals that could be exploited for targeted therapy of cancer. PGE2 signals through EP1, EP2, EP3, and EP4 that belong to the superfamily of GPCR that have been demonstrated to signal through G proteins and βArrestins. In the first part of this thesis project we determined the role of βArrestins in PGE2-regulated cancer cell migration. We report that the COX-2 effector PGE2 signals selectively via EP4 to enhance A549 lung cancer cell migration. We further find that this mode of signaling requires the presence of βArrestin1 and tyrosine kinase c-Src activity. Hence, this study provides preclinical-based rationale for the selective targeting of EP4 to inhibit PGE2-induced lung cancer cell migration. In the second part of this thesis project we determined the role of G protein-coupled receptor kinase 5 (GRK5) in cancer cell proliferation and tumor growth. Recent studies have implicated distinct GRK roles in the regulation of non-GPCR substrates, some of which have well-defined roles in cancer progression such as tumor suppressor p53. Here we report that GRK5 is required for prostate cancer cell cycle progression, cell proliferation, and prostate tumor growth. We identified HDAC4 as a novel GRK5 substrate, whose gene and protein expression is regulated by its kinase activity. In addition, we found that serine 246 residue of HDAC4 is phosphorylated by GRK5, a site known to regulate HDAC4 activity and subcellular localization. GRK5 can also phosphorylate an HDAC4 fragment (419-670 amino acid residues) that also contains two important regulatory serine phosphorylation sites. As many studies have shown HDAC4 involvement in cancer, our findings may provide a possible mechanism of HDAC4 regulation by GRK5.
Affiliation:
Department of Neuroscience and Regenerative Medicine
Issue Date:
Dec-2010
URI:
http://hdl.handle.net/10675.2/317390
Type:
Dissertation
Language:
en_US
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorKim, Jae IIen
dc.date.accessioned2014-05-23T18:54:15Z-
dc.date.available2014-05-23T18:54:15Z-
dc.date.issued2010-12-
dc.identifier.urihttp://hdl.handle.net/10675.2/317390-
dc.description.abstractCancer is a leading cause of death worldwide, accounting for nearly seven million deaths per year. Available clinical data establish a protective effect of COX-2 inhibition on human cancer progression, but the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer therapeutics. Major COX-2 effectors are prostaglandins and we explored the idea that PGE2 promotes mitogenic signals that could be exploited for targeted therapy of cancer. PGE2 signals through EP1, EP2, EP3, and EP4 that belong to the superfamily of GPCR that have been demonstrated to signal through G proteins and βArrestins. In the first part of this thesis project we determined the role of βArrestins in PGE2-regulated cancer cell migration. We report that the COX-2 effector PGE2 signals selectively via EP4 to enhance A549 lung cancer cell migration. We further find that this mode of signaling requires the presence of βArrestin1 and tyrosine kinase c-Src activity. Hence, this study provides preclinical-based rationale for the selective targeting of EP4 to inhibit PGE2-induced lung cancer cell migration. In the second part of this thesis project we determined the role of G protein-coupled receptor kinase 5 (GRK5) in cancer cell proliferation and tumor growth. Recent studies have implicated distinct GRK roles in the regulation of non-GPCR substrates, some of which have well-defined roles in cancer progression such as tumor suppressor p53. Here we report that GRK5 is required for prostate cancer cell cycle progression, cell proliferation, and prostate tumor growth. We identified HDAC4 as a novel GRK5 substrate, whose gene and protein expression is regulated by its kinase activity. In addition, we found that serine 246 residue of HDAC4 is phosphorylated by GRK5, a site known to regulate HDAC4 activity and subcellular localization. GRK5 can also phosphorylate an HDAC4 fragment (419-670 amino acid residues) that also contains two important regulatory serine phosphorylation sites. As many studies have shown HDAC4 involvement in cancer, our findings may provide a possible mechanism of HDAC4 regulation by GRK5.en
dc.language.isoen_USen
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.-
dc.titleΒeta-Arrestin1 and G Protein-Coupled Receptor Kinase5 Regulate Cancer Progressionen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neuroscience and Regenerative Medicineen
cr.approval.ethicalhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/849292015?accountid=12365en
dc.description.advisorDaaka, Yehia-
dc.description.committeeNie, Zhongzhen; Schoenlein, Patricia;Lambert, Nevin ;Huang, Shuang; Browning, Darren; Baban, Babak;Caughman, Gretchen; Inscho, Edward.-
dc.description.degreeDoctor of Philosphy (PhD)-
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