Role of Protein Kinase D in Keratinocyte Proliferation and Epidermal Tumorigenesis

Hdl Handle:
http://hdl.handle.net/10675.2/344092
Title:
Role of Protein Kinase D in Keratinocyte Proliferation and Epidermal Tumorigenesis
Authors:
Arun, Senthil N.
Abstract:
Skin is an excellent model to study carcinogenesis as the cells that comprise the outer layer of the skin, the epidermal keratinocytes exhibit an inherent pattern of proliferation and differentiation. Any deviation from this physiological process results in hyperproliferative diseases such as non-melanoma skin cancers and psoriasis. Protein kinase D (PKD) is a serine/threonine kinase that has been implicated in numerous cellular processes. Previous studies performed in our laboratory show that PKD levels are upregulated in human basal cell carcinomas (BCC) and in a neoplastic mouse keratinocyte line, supporting a possible tumorigenic role for PKD in epidermis. In addition, PKD activity appears to be correlated with epidermal keratinocyte proliferation. Thus, compounds that inhibit PKD and protein kinase C (PKC), but not those that inhibit only PKC, stimulate differentiation. Mouse keratinocytes treated with the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), exhibit an initial decrease in PKD activation followed by a recovery. Thus, the biphasic response of PKD activation after TPA treatment seems to mirror the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes and epidermis in vivo, and we hypothesized that PKD may contribute to TPA-induced tumorigenesis. Indeed, we found that the PKC/PKD inhibitor G66976 blocked the increase in DNA specific activity induced by chronic TPA without affecting the initial TPA-elicited differentiation. In contrast, the PKC inhibitor G66983 prevented both the initial induction of differentiation and the subsequent promotion of proliferation in response to TPA. Our results support the idea that PKD may be involved in tumor formation in the epidermis.The biggest risk factor for the development of skin tumors in humans is sun exposure, leading us to investigate the ability of ultraviolet B (UVB) exposure to activate PKD. Our data suggest that irradiation of primary mouse keratinocytes with UVB resulted in activation of PKD in a time- and dose-dependent manner, via ROS generation. In addition, PKD overexpression protected keratinocytes from UVB-induced apoptosis. Collectively, our data suggest that PKD plays an important role in protecting keratinocytes from UVB-induced apoptosis and provide a link between sun exposure, BCC and PKD.
Affiliation:
Department of Physiology
Issue Date:
May-2010
URI:
http://hdl.handle.net/10675.2/344092
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/250280159?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations; Department of Physiology Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorArun, Senthil N.en
dc.date.accessioned2015-02-03T20:56:16Z-
dc.date.available2015-02-03T20:56:16Z-
dc.date.issued2010-05-
dc.identifier.urihttp://hdl.handle.net/10675.2/344092-
dc.description.abstractSkin is an excellent model to study carcinogenesis as the cells that comprise the outer layer of the skin, the epidermal keratinocytes exhibit an inherent pattern of proliferation and differentiation. Any deviation from this physiological process results in hyperproliferative diseases such as non-melanoma skin cancers and psoriasis. Protein kinase D (PKD) is a serine/threonine kinase that has been implicated in numerous cellular processes. Previous studies performed in our laboratory show that PKD levels are upregulated in human basal cell carcinomas (BCC) and in a neoplastic mouse keratinocyte line, supporting a possible tumorigenic role for PKD in epidermis. In addition, PKD activity appears to be correlated with epidermal keratinocyte proliferation. Thus, compounds that inhibit PKD and protein kinase C (PKC), but not those that inhibit only PKC, stimulate differentiation. Mouse keratinocytes treated with the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), exhibit an initial decrease in PKD activation followed by a recovery. Thus, the biphasic response of PKD activation after TPA treatment seems to mirror the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes and epidermis in vivo, and we hypothesized that PKD may contribute to TPA-induced tumorigenesis. Indeed, we found that the PKC/PKD inhibitor G66976 blocked the increase in DNA specific activity induced by chronic TPA without affecting the initial TPA-elicited differentiation. In contrast, the PKC inhibitor G66983 prevented both the initial induction of differentiation and the subsequent promotion of proliferation in response to TPA. Our results support the idea that PKD may be involved in tumor formation in the epidermis.The biggest risk factor for the development of skin tumors in humans is sun exposure, leading us to investigate the ability of ultraviolet B (UVB) exposure to activate PKD. Our data suggest that irradiation of primary mouse keratinocytes with UVB resulted in activation of PKD in a time- and dose-dependent manner, via ROS generation. In addition, PKD overexpression protected keratinocytes from UVB-induced apoptosis. Collectively, our data suggest that PKD plays an important role in protecting keratinocytes from UVB-induced apoptosis and provide a link between sun exposure, BCC and PKD.en
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/250280159?accountid=12365en
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.en
dc.subjectEpidermisen
dc.subjectPhorbol Estersen
dc.subjectProtein Kinase Cen
dc.subjectProtein Kinase Den
dc.subjectSkinen
dc.subjectTumorigenesisen
dc.subjectUVBen
dc.titleRole of Protein Kinase D in Keratinocyte Proliferation and Epidermal Tumorigenesisen
dc.typeDissertationen
dc.contributor.departmentDepartment of Physiologyen
dc.description.advisorBollag, Wendy B.en
dc.description.committeeWatah, John; Lewis, Jill; Bieberish, Erhard; Hsu, Stephenen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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