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J. Biol. Chem., Vol. 282, Issue 4, 2237-2249, January 26, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/4/2237    most recent M608642200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lindsey, S. Articles by Eklund, E. A. Search for Related Content PubMed PubMed Citation Articles by Lindsey, S. Articles by Eklund, E. A. Social Bookmarking                      What's this?

Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91^PHOX and p67^PHOX*

Stephan Lindsey, Weiqi Huang, Hao Wang, Elizabeth Horvath, Chunliu Zhu, and Elizabeth A. Eklund¹

From the Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611 and the Jesse Brown Veterans Affairs Medical Center, Lakeside Division, Chicago, Illinois 60612

The CYBB and NCF2 genes encode the phagocyte oxidase proteins gp91^PHOX and p67^PHOX, respectively. These genes are transcribed after the promyelocyte stage of differentiation, and transcription continues until cell death. In undifferentiated myeloid cells, homologous cis-elements in the CYBB and NCF2 genes are repressed by the homeodomain transcription factor HoxA10. During cytokine-induced myelopoiesis, tyrosine phosphorylation of HoxA10 decreases binding affinity for the CYBB and NCF2 cis-elements. This abrogates HoxA10-induced transcriptional repression as differentiation proceeds. Therefore, mechanisms involved in differentiation stage-specific HoxA10 tyrosine phosphorylation are of interest because HoxA10 phosphorylation modulates myeloid-specific gene transcription. In this study, we found that HoxA10 is a substrate for SHP2 protein-tyrosine phosphatase in undifferentiated myeloid cells. In contrast, HoxA10 is a substrate for a constitutively active mutant form of SHP2 in both undifferentiated and differentiating myeloid cells. Expression of such SHP2 mutants results in persistent HoxA10 repression of CYBB and NCF2 transcription during myelopoiesis. Both HoxA10 overexpression and activating SHP2 mutations have been described in human myeloid malignancies. Therefore, our results suggest that these mutations could cooperate, leading to decreased myeloid-specific gene transcription and functional differentiation block in myeloid cells with both defects.

Received for publication, September 7, 2006 , and in revised form, November 22, 2006.

^* 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 To whom correspondence should be addressed: Feinberg School of Medicine, Olson Pavilion, Rm. 8524, 710 North Fairbanks Ct., Chicago, IL 60611. Tel.: 312-503-4625; Fax: 312-908-5717; E-mail: e-eklund{at}northwestern.edu.

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				C. Zhu, S. Lindsey, I. Konieczna, and E. A. Eklund Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation J. Leukoc. Biol., March 1, 2008; 83(3): 680 - 691. [Abstract] [Full Text] [PDF]