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

J. Biol. Chem., Vol. 281, Issue 5, 2441-2450, February 3, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/5/2441    most recent M511173200v1 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 Hickey, F. B. Articles by Cotter, T. G. Search for Related Content PubMed PubMed Citation Articles by Hickey, F. B. Articles by Cotter, T. G. Social Bookmarking                      What's this?

BCR-ABL Regulates Phosphatidylinositol 3-Kinase-p110 Transcription and Activation and Is Required for Proliferation and Drug Resistance^*

From the Department of Biochemistry, Biosciences Institute, University College Cork, Cork, Ireland

The BCR-ABL oncogene is the hallmark of chronic myeloid leukemia, a clonal hematopoietic stem cell disorder. BCR-ABL displays constitutive tyrosine kinase activity, required for its transformation ability. Although the molecular mechanisms behind this malignancy are not fully understood, a role for phosphatidylinositol (PI) 3-kinase has been repeatedly described. Here we report the specific up-regulation of the class I_B catalytic subunit of PI 3-kinase (p110) in response to BCR-ABL expression. We demonstrate that this upregulation is due to increased transcription and is dependent on both PI 3-kinase and MEK activity. We performed in vitro kinase activity assays and show that BCR-ABL also leads to increased p110 activity and that this activation requires both G protein-coupled receptor and Ras signaling. In addition, by transfection of cells with dominant negative p110, we determined that this specific PI 3-kinase isoform is involved in both proliferation and the apoptosis resistance associated with chronic myeloid leukemia. The data presented here define for the first time the ability of BCR-ABL to alter the expression levels of PI 3-kinase isoforms and also demonstrate a previously unreported link between BCR-ABL and p110.

Received for publication, October 13, 2005

^* This work was supported by the Higher Education Authority of Ireland, the Children's Leukemia Research Project, and Cancer Research Ireland. 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 on-line version of this article (available at http://www.jbc.org) contains two figures.

¹ To whom correspondence should be addressed. Tel.: 353-21-4901321; Fax: 353-21-4901382; E-mail: t.cotter{at}ucc.ie.

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

This article has been cited by other articles:

				N. T. Ihle and G. Powis Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy Mol. Cancer Ther., January 1, 2009; 8(1): 1 - 9. [Abstract] [Full Text] [PDF]

				S. Kang, A. Denley, B. Vanhaesebroeck, and P. K. Vogt Oncogenic transformation induced by the p110beta, -{gamma}, and -{delta} isoforms of class I phosphoinositide 3-kinase PNAS, January 31, 2006; 103(5): 1289 - 1294. [Abstract] [Full Text] [PDF]