The Metastasis-Associated Gene Prl-3 Is a p53 Target Involved in Cell-Cycle Regulation

Shashwati Basak; Suzanne B.R. Jacobs; Adam J. Krieg; Navneeta Pathak; Qi Zeng; Philipp Kaldis; Amato J. Giaccia; Laura D. Attardi

doi:10.1016/j.molcel.2008.04.002

The Metastasis-Associated Gene Prl-3 Is a p53 Target Involved in Cell-Cycle Regulation

Shashwati Basak, Suzanne B.R. Jacobs, Adam J. Krieg, Navneeta Pathak, Qi Zeng, Philipp Kaldis, Amato J. Giaccia, Laura D. Attardi

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

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 G₁ 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 language	English (US)
Pages (from-to)	303-314
Number of pages	12
Journal	Molecular Cell
Volume	30
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2008.04.002
State	Published - May 9 2008
Externally published	Yes

Keywords

CELLCYCLE

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2008.04.002

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@article{c9205f896f5246c4b82d6735e1d734dc,

title = "The Metastasis-Associated Gene Prl-3 Is a p53 Target Involved in Cell-Cycle Regulation",

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 G1 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.",

keywords = "CELLCYCLE",

author = "Shashwati Basak and Jacobs, {Suzanne B.R.} and Krieg, {Adam J.} and Navneeta Pathak and Qi Zeng and Philipp Kaldis and Giaccia, {Amato J.} and Attardi, {Laura D.}",

note = "Funding Information: We thank S. Artandi for the p19 Arf−/− MEFs, N. Hay for the Akt1-/;Akt2 −/− MEFs, S. Lessnick for the pSIRIPP plasmid, P. Jackson for the pCS2 plasmid, A. Brunet for the FLAG-Foxo3a plasmid, and T. Stearns for the γ-tubulin antibody. We thank S. Artandi, J. Sage, A. Brunet, R. Shaw, and T. M. Johnson for critically reading the manuscript. We thank T.M. Johnson and B.T. Nguyen for technical help. This work was supported by a Stanford Dean's postdoctoral fellowship and a Susan G. Komen postdoctoral fellowship to S.B., the Giannini Family Foundation to S.B.R.J., and the Damon Runyon Cancer Research Foundation and the Donald E. and Delia B. Baxter Foundation to L.D.A. ",

year = "2008",

month = may,

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doi = "10.1016/j.molcel.2008.04.002",

language = "English (US)",

volume = "30",

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journal = "Molecular Cell",

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AU - Basak, Shashwati

AU - Jacobs, Suzanne B.R.

AU - Krieg, Adam J.

AU - Pathak, Navneeta

AU - Zeng, Qi

AU - Kaldis, Philipp

AU - Giaccia, Amato J.

AU - Attardi, Laura D.

N1 - Funding Information: We thank S. Artandi for the p19 Arf−/− MEFs, N. Hay for the Akt1-/;Akt2 −/− MEFs, S. Lessnick for the pSIRIPP plasmid, P. Jackson for the pCS2 plasmid, A. Brunet for the FLAG-Foxo3a plasmid, and T. Stearns for the γ-tubulin antibody. We thank S. Artandi, J. Sage, A. Brunet, R. Shaw, and T. M. Johnson for critically reading the manuscript. We thank T.M. Johnson and B.T. Nguyen for technical help. This work was supported by a Stanford Dean's postdoctoral fellowship and a Susan G. Komen postdoctoral fellowship to S.B., the Giannini Family Foundation to S.B.R.J., and the Damon Runyon Cancer Research Foundation and the Donald E. and Delia B. Baxter Foundation to L.D.A.

PY - 2008/5/9

Y1 - 2008/5/9

N2 - 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 G1 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.

AB - 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 G1 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.

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ER -

The Metastasis-Associated Gene Prl-3 Is a p53 Target Involved in Cell-Cycle Regulation

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Keywords

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