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

J. Biol. Chem., Vol. 282, Issue 34, 24633-24641, August 24, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/34/24633    most recent M703105200v1 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 Varmeh-Ziaie, S. Articles by Manfredi, J. J. Search for Related Content PubMed PubMed Citation Articles by Varmeh-Ziaie, S. Articles by Manfredi, J. J. Social Bookmarking                      What's this?

The Dual Specificity Phosphatase Cdc25B, but Not the Closely Related Cdc25C, Is Capable of Inhibiting Cellular Proliferation in a Manner Dependent upon Its Catalytic Activity^*

From the Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029

Cdc25B and Cdc25C are closely related dual specificity phosphatases that activate cyclin-dependent kinases by removal of inhibitory phosphorylations, thereby triggering entry into mitosis. Cdc25B, but not Cdc25C, has been implicated as an oncogene and been shown to be overexpressed in a variety of human tumors. Surprisingly, ectopic expression of Cdc25B, but not Cdc25C, inhibits cell proliferation in long term assays. Chimeric proteins generated from the two phosphatases show that the anti-proliferative activity is associated with the C-terminal end of Cdc25B. Indeed, the catalytic domain of Cdc25B is sufficient to suppress cell viability in a manner partially dependent upon its C-terminal 26 amino acids that is shown to influence substrate binding. Mutation analysis demonstrates that both the phosphatase activity of Cdc25B as well as its ability to interact with its substrates contribute to the inhibition of cell proliferation. These results demonstrate key differences in the biological activities of Cdc25B and Cdc25C caused by differential substrate affinity and recognition. This also argues that the antiproliferative activity of Cdc25B needs to be overcome for it to act as an oncogene during tumorigenesis.

Received for publication, April 12, 2007 , and in revised form, June 18, 2007.

^* This work was supported by NCI, National Institutes of Health Grant CA086001 and Department of Defense Breast Cancer Research Program Grant W81XWH-05-1-0305. 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.

¹ Present address: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Ave., New York, NY 10021.

² To whom correspondence should be addressed: Dept. of Oncological Sciences, Box 1130, Mount Sinai School of Medicine, New York, NY 10029. Tel.: 212-659-5495; Fax: 212-849-2446; E-mail: james.manfredi{at}mssm.edu.

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

This article has been cited by other articles:

				S. Varmeh and J. J. Manfredi Inappropriate Activation of Cyclin-dependent Kinases by the Phosphatase Cdc25b Results in Premature Mitotic Entry and Triggers a p53-dependent Checkpoint J. Biol. Chem., April 3, 2009; 284(14): 9475 - 9488. [Abstract] [Full Text] [PDF]

				S. Varmeh and J. J. Manfredi Overexpression of the dual specificity phosphatase, Cdc25C, confers sensitivity on tumor cells to doxorubicin-induced cell death Mol. Cancer Ther., December 1, 2008; 7(12): 3789 - 3799. [Abstract] [Full Text] [PDF]