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The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation

Basak, Shashwati ; Jacobs, Suzanne B.R. ; Krieg, Adam J. ; Pathak, Navneeta ; Zeng, Qi ; Kaldis, Philipp LU orcid ; Giaccia, Amato J. and Attardi, Laura D. (2008) In Molecular Cell 30(3). p.303-314
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... (More)

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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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
CELLCYCLE
in
Molecular Cell
volume
30
issue
3
pages
303 - 314
publisher
Cell Press
external identifiers
  • pmid:18471976
  • scopus:42949121716
ISSN
1097-2765
DOI
10.1016/j.molcel.2008.04.002
language
English
LU publication?
no
id
b65c7eca-f16b-43c4-8749-3434e0e37e2b
date added to LUP
2019-09-18 14:13:54
date last changed
2024-04-30 21:50:31
@article{b65c7eca-f16b-43c4-8749-3434e0e37e2b,
  abstract     = {{<p>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<sub>1</sub> 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.</p>}},
  author       = {{Basak, Shashwati and Jacobs, Suzanne B.R. and Krieg, Adam J. and Pathak, Navneeta and Zeng, Qi and Kaldis, Philipp and Giaccia, Amato J. and Attardi, Laura D.}},
  issn         = {{1097-2765}},
  keywords     = {{CELLCYCLE}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{3}},
  pages        = {{303--314}},
  publisher    = {{Cell Press}},
  series       = {{Molecular Cell}},
  title        = {{The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation}},
  url          = {{http://dx.doi.org/10.1016/j.molcel.2008.04.002}},
  doi          = {{10.1016/j.molcel.2008.04.002}},
  volume       = {{30}},
  year         = {{2008}},
}