12-O-Tetradecanoylphorbol-13-acetate and UV Radiation-induced Nucleoside Diphosphate Protein Kinase B Mediates Neoplastic Transformation of Epidermal Cells

Sung Jen Wei, Carol S. Trempus, Robin C. Ali, Laura A. Hansen, Raymond W. Tennant

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The molecular changes associated with early skin carcinogenesis are largely unknown. We have previously identified 11 genes whose expression was up- or down-regulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin keratinocyte progenitor cells (Wei, S.-J., Trempus, C. S., Cannon, R. E., Bortner, C. D., and Tennant, R. W. (2003) J. Biol. Chem. 278, 1758-1768). Here, we show an induction of a nucleoside diphosphate protein kinase B (NDPK-B) gene in response to TPA or UV radiation (UVR). TPA or UVR significantly induced the expression of NDPK-B both in vivo hyperplastic mouse skin and in vitro mouse JB6 Cl 41-5a epidermal cells. Indeed, this gene was also up-regulated in TPA or UVR-mediated skin tumors including papillomas, spindle cell tumors, and squamous cell carcinomas, relative to adjacent normal skins. Functional studies by constitutive expression of nm23-M2/NDPK-B in TPA susceptible JB6 Cl 41-5a and TPA-resistant JB6 Cl 30-7b preneoplastic epidermal cell lines showed a remarkable gene dosage-dependent increase in foci-forming activity, as well as an enhancement in the efficiency of neoplastic transfomation of these cells in soft agar but no effect on proliferation in monolayer cultures. Interestingly, stable transfection of the nm23-M2/NDPK-B delRGD or G106A mutant gene in JB6 Cl 41-5a cells selectively abrogated NDPK-B-induced cellular transformation, implicating a possible Arg105-Gly106-Asp107 regulatory role in early skin carcinogenesis.

Original languageEnglish
Pages (from-to)5993-6004
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number7
DOIs
StatePublished - Feb 13 2004

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NM23 Nucleoside Diphosphate Kinases
Neoplastic Cell Transformation
Proto-Oncogene Proteins c-akt
Diphosphates
Tetradecanoylphorbol Acetate
Nucleosides
Ultraviolet radiation
Skin
Acetates
Cells
Radiation
Genes
Tumors
Carcinogenesis
Gene Dosage
Papilloma
Keratinocytes
Gene expression
Agar
Transfection

All Science Journal Classification (ASJC) codes

  • Biochemistry

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12-O-Tetradecanoylphorbol-13-acetate and UV Radiation-induced Nucleoside Diphosphate Protein Kinase B Mediates Neoplastic Transformation of Epidermal Cells. / Wei, Sung Jen; Trempus, Carol S.; Ali, Robin C.; Hansen, Laura A.; Tennant, Raymond W.

In: Journal of Biological Chemistry, Vol. 279, No. 7, 13.02.2004, p. 5993-6004.

Research output: Contribution to journalArticle

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abstract = "The molecular changes associated with early skin carcinogenesis are largely unknown. We have previously identified 11 genes whose expression was up- or down-regulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin keratinocyte progenitor cells (Wei, S.-J., Trempus, C. S., Cannon, R. E., Bortner, C. D., and Tennant, R. W. (2003) J. Biol. Chem. 278, 1758-1768). Here, we show an induction of a nucleoside diphosphate protein kinase B (NDPK-B) gene in response to TPA or UV radiation (UVR). TPA or UVR significantly induced the expression of NDPK-B both in vivo hyperplastic mouse skin and in vitro mouse JB6 Cl 41-5a epidermal cells. Indeed, this gene was also up-regulated in TPA or UVR-mediated skin tumors including papillomas, spindle cell tumors, and squamous cell carcinomas, relative to adjacent normal skins. Functional studies by constitutive expression of nm23-M2/NDPK-B in TPA susceptible JB6 Cl 41-5a and TPA-resistant JB6 Cl 30-7b preneoplastic epidermal cell lines showed a remarkable gene dosage-dependent increase in foci-forming activity, as well as an enhancement in the efficiency of neoplastic transfomation of these cells in soft agar but no effect on proliferation in monolayer cultures. Interestingly, stable transfection of the nm23-M2/NDPK-B delRGD or G106A mutant gene in JB6 Cl 41-5a cells selectively abrogated NDPK-B-induced cellular transformation, implicating a possible Arg105-Gly106-Asp107 regulatory role in early skin carcinogenesis.",
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