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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.

Original publication




Journal article


Mol Cell

Publication Date





303 - 314


Animals, Cell Cycle, Cells, Cultured, Colorectal Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Fibroblasts, Gene Expression Regulation, Humans, Immediate-Early Proteins, Mice, Mice, Knockout, Neoplasm Invasiveness, Neoplasm Metastasis, Oligonucleotide Array Sequence Analysis, Phosphatidylinositol 3-Kinases, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction, Tumor Suppressor Protein p53