Cell Cycle Balancing Act

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

The tumor suppressor protein p53 responds to such cell stress-inducing stimuli as DNA damage and hypoxia. The resulting nuclear accumulation of p53 triggers the repression or activation of the appropriate genes to lead to apoptosis or cell-cycle arrest, thus halting cell proliferation. In a search for new p53 target genes, Basak et al. exposed various primary cell types from wild-type or p53-deficient mice to DNA-damaging stimuli such as Doxorubicin or irradiation. Microarray analyses showed that expression of the gene Prl-3 was induced by these stimuli in a p53-dependent manner, and Western blotting showed that Prl-3 protein increased in abundance accordingly. This was unexpected because Prl-3, a protein phosphatase, is known to promote tumor metastasis. Chromatin immunoprecipitation assays demonstrated that p53 bound to Prl-3, and reporter assays in wild-type and p53-deficient mouse embryo fibroblasts (MEFs) showed that Prl-3 was a transcriptional target of p53. Proliferation assays showed that Prl-3, when overexpressed in MEFs, triggered cell-cycle arrest but not apoptosis. Western blotting analysis demonstrated that overexpression of Prl-3 in human fibrosarcoma cells initially led to activation of the kinase Akt, which is known to enhance cell proliferation. However, as Prl-3 abundance increased with time, it inhibited Akt activity through a negative-feedback mechanism, leading to cell-cycle arrest. Indeed, Prl-3 could not induce cell-cycle arrest in Akt-deficient MEFs. To add even more complexity, knockdown of Prl-3 in MEFs also led to cell-cycle arrest, in a p53-dependent manner. Together, these data suggest that the abundance of Prl-3, a new target of p53 (see commentary by Hinds), must be tightly controlled for normal cell-cycle progression.

S. Basak, S. B. R. Jacobs, A. J. Krieg, N. Pathak, Q. Zeng, P. Kaldis, A. J. Giaccia, L. D. Attardi, The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation. Mol. Cell 30, 303-314 (2008). [PubMed]

P. W. Hinds, Too much of a good thing: The Prl-3 in p53’s oyster. Mol. Cell 30, 260-261 (2008). [PubMed]

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