HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 18, 12076-12084, May 2, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/18/12076    most recent M801571200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, X. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Wang, X. Articles by Cao, X. Social Bookmarking                      What's this?

IPP5, a Novel Protein Inhibitor of Protein Phosphatase 1, Promotes G₁/S Progression in a Thr-40-dependent Manner^*

Xiaojian Wang¹, Bin Liu¹, Nan Li, Hongzhe Li, Jianming Qiu, Yuanyuan Zhang, and Xuetao Cao²

From the Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433 and Institute of Immunology, Zhejiang University, Hangzhou 310058, China

Protein phosphatase 1 (PP1) is a major serine/threonine phosphatase that controls gene expression and cell cycle progression. Here we describe the characterization of a novel inhibitory molecule for PP1, human inhibitor-5 of protein phosphatase 1 (IPP5). We find that IPP5, containing the PP1 inhibitory subunits, specifically interacts with the PP1 catalytic subunit and inhibits PP1 phosphatase activity. Furthermore, the mutation of Thr-40 within the inhibitory subunit of IPP5 into Ala eliminates the phosphorylation of IPP5 by protein kinase A and its inhibitor activity to PP1, whereas the mutation of Thr-40 within a truncated form of IPP5 into Asp can serve as a dominant active form of IPP5 in inhibiting PP1 activity. In IPP5-negative SW480 and IPP5-highly positive SW620 human colon cancer cells, we find that overexpression of IPP5 promotes the growth and accelerates the G₁-S transition of SW480 cells in a Thr-40-dependent manner, which could be reversed by downregulation of the PP1 expression. Moreover, silencing of IPP5 inhibits the growth of SW620 cells both in vitro and in nude mice possibly by inducing G₀/G₁ arrest but not by promoting apoptosis. According to its role in the promotion of cell cycle progression and cell growth, IPP5 up-regulates the expression of cyclin E and the phosphorylated form of retinoblastoma protein. Our findings suggest that IPP5, by acting as an inhibitory molecule for PP1, can promote tumor cell growth and cell cycle progression, and may be a promising target in cancer therapeutics in IPP5-highly expressing tumor cells.

Received for publication, February 27, 2008

^* This work was supported by Shanghai Committee of Science and Technology Grant 06DJ14011, National High Biotechnology Development Program of China Grant 2006AA02A305, and the National Natural Science Foundation of China Grant 30721091. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF494535.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China. Fax: 86-21-6538-2502; E-mail: caoxt{at}public3.sta.net.cn.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Popescu, Z. Gurel, T. Ronni, C. Song, K. Y. Hung, K. J. Payne, and S. Dovat Ikaros Stability and Pericentromeric Localization Are Regulated by Protein Phosphatase 1 J. Biol. Chem., May 15, 2009; 284(20): 13869 - 13880. [Abstract] [Full Text] [PDF]