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J. Biol. Chem., Vol. 278, Issue 29, 26466-26473, July 18, 2003
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From the Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain
Cells must increase their mass in coordination with cell cycle progression to ensure that their size and macromolecular composition remain constant for any given proliferation rate. To this end, growth factors activate early signaling cascades that simultaneously promote cell mass increase and induce cell cycle entry. Nonetheless, the mechanism that controls the concerted regulation of cell growth and cell cycle entry in mammals remains unknown. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B pathway regulates cell cycle entry by inactivating forkhead transcription factors and promoting cyclin D synthesis. PI3K/protein kinase B-derived signals also affect activation of p70 S6 kinase and the mammalian target of rapamycin, enzymes involved in cell growth control. We previously showed that enhancement of PI3K activation accelerates cell cycle entry, whereas reduction of PI3K activation retarded this process. Here we examined whether expression of different PI3K mutants affects cell growth during cell division. We show that diminishing or enhancing the magnitude of PI3K activation in a transient manner reduces or increases, respectively, the protein synthesis rate. Alteration of cell growth and cell cycle entry by PI3K forms appears to be concerted, because it results in lengthening or shortening of cell division time without altering cell size. In support of a central role for PI3K in growth control, expression of a deregulated, constitutive active PI3K mutant affects p70 S6 kinase and mammalian target of rapamycin activities and increases cell size. Together, the results show that transient PI3K activation regulates cell growth and cell cycle in a coordinated manner, which in turn controls cell division time.
Received for publication, January 21, 2003 , and in revised form, April 2, 2003.
* This work was supported by Grant QLRT-2001-02171 from the European Union, Grant 08.3/0030 from the Community of Madrid, and Grant SAF2001-2278 from the Spanish Dirección General de Ciencia y Desarrollo Tecnológico. The Department of Immunology and Oncology was founded and is supported by the Spanish Council for Scientific Research and by the Pharmacia Corporation. 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.
To whom correspondence should be addressed: Dept. of Immunology and Oncology,
Centro Nacional de Biotecnología/CSIC, Carretera de Colmenar Km 15,
Cantoblanco, Madrid E-28049, Spain. Tel.: 34-91-585-4849; Fax: 34-91-372-0493;
E-mail:
acarrera{at}cnb.uam.es.
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