Abstract
The Ets family of transcription factors are important downstream targets in cellular transformation, as altering Ets activity has been found to reverse the transformed phenotype of Ras transformed mouse fibroblasts and of several human tumor cell lines. To determine whether Ets factors are important targets in the largely uncharacterized aberrant signaling in prostate cancer, we have altered Ets activity in the prostate tumor cell line PPC-1, by stable expression of either full-length Ets2, or a dominant inhibitor of Ets activity, the Ets2 DNA binding domain (Ets2DBD). Analysis of multiple independent clonal cell lines revealed that expression of either Ets2 or the Ets2DBD inhibited the anchorage-independent growth of PPC-1 cells up to 20-fold. In contrast to our previous findings with Ras-transformed NIH3T3 cells, PPC-1 cell lines expressing either Ets2 or the EtsDBD exhibited slower attached cell growth, increased Ets-dependent gene expression, and up to a 10-fold increase in apoptotic cell death. The p21cip gene was identified as a potential target of altered Ets signaling. Interestingly, the two distinct Ets2 constructs had strikingly different effects on in vitro invasiveness. Expression of the Ets2DBD almost completely blocked PPC-1 cell invasion through Matrigel, whereas over-expression of full-length Ets2 did not inhibit invasion. Overall, these results demonstrate that the balance of Ets factor activity can regulate multiple aspects of the transformed phenotype of PPC-1 prostate tumor cells, including anchorage-independent growth, survival, and invasiveness.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Apoptosis / physiology
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Binding Sites
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Adhesion
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Cell Cycle Proteins*
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Cell Division / physiology
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Cell Movement / physiology
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Cell Survival / physiology
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Cell Transformation, Neoplastic*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / biosynthesis
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DNA-Binding Proteins*
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Gene Expression Regulation, Neoplastic
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Genes, Reporter
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Humans
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Male
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Mice
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Microtubule-Associated Proteins / biosynthesis
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Neoplasm Invasiveness
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / physiology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology*
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Protein Structure, Tertiary
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Proto-Oncogene Protein c-ets-2
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Repressor Proteins*
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factors*
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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ERF protein, human
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ETS2 protein, human
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Ets2 protein, mouse
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Microtubule-Associated Proteins
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Peptide Fragments
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Proto-Oncogene Protein c-ets-2
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Proto-Oncogene Proteins
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27