Abstract
The p53 tumor suppressor restricts tumorigenesis through the transcriptional activation of target genes involved in cell-cycle arrest and apoptosis. Here, we identify Prl-3 (phosphatase of regenerating liver-3) as a p53-inducible gene. Whereas previous studies implicated Prl-3 in metastasis because of its overexpression in metastatic human colorectal cancer and its ability to promote invasiveness and motility, we demonstrate here that Prl-3 is an important cell-cycle regulator. Consistent with a role in DNA damage-induced cell-cycle arrest, Prl-3 overexpression induces G(1) arrest downstream of p53 by triggering a PI3K-Akt-activated negative feedback loop. Surprisingly, attenuation of Prl-3 expression also elicits an arrest response, suggesting that basal level Prl-3 expression is pivotal for normal cell-cycle progression. Our findings highlight key dose-dependent functions of Prl-3 in both positive and negative regulation of cell-cycle progression and provide insight into Prl-3's role in cancer progression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle / physiology*
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Cells, Cultured
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Fibroblasts / cytology
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Fibroblasts / physiology
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Gene Expression Regulation
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Humans
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Immediate-Early Proteins / genetics*
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Immediate-Early Proteins / metabolism
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Mice
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Mice, Knockout
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Neoplasm Invasiveness / genetics
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Neoplasm Metastasis / genetics*
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Oligonucleotide Array Sequence Analysis
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Tyrosine Phosphatases / genetics*
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Protein Tyrosine Phosphatases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Signal Transduction / physiology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Immediate-Early Proteins
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Ptp4a3 protein, mouse
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Tumor Suppressor Protein p53
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Protein Tyrosine Phosphatases