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J. Biol. Chem., Vol. 283, Issue 45, 31163-31171, November 7, 2008

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c-Fos Activates Glucosylceramide Synthase and Glycolipid Synthesis in PC12 Cells^*

From the Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC (UNC-Consejo Nacional de Investigaciones Científicas y Técnicas), Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torres esq. M. Allende, Ciudad Universitaria, Córdoba X5000HUA, Argentina

It has been demonstrated that c-Fos has, in addition to its well recognized AP-1 transcription factor activity, the capacity to associate to the endoplasmic reticulum and activate key enzymes involved in the synthesis of phospholipids required for membrane biogenesis during cell growth and neurite formation. Because membrane genesis requires the coordinated supply of all its integral membrane components, the question emerges as to whether c-Fos also activates the synthesis of glycolipids, another ubiquitous membrane component. We show that c-Fos activates the metabolic labeling of glycolipids in differentiating PC12 cells. Specifically, c-Fos activates the enzyme glucosylceramide synthase (GlcCerS), the product of which, GlcCer, is the first glycosylated intermediate in the pathway of synthesis of glycolipids. By contrast, the activities of GlcCer galactosyltransferase 1 and lactosylceramide sialyltransferase 1 are essentially unaffected by c-Fos. Co-immunoprecipitation experiments in cells co-transfected with c-Fos and a V5-tagged version of GlcCerS evidenced that both proteins participate in a physical association. c-Fos expression is tightly regulated by specific environmental cues. This strict regulation assures that lipid metabolism activation will occur as a response to cell requirements thus pointing to c-Fos as an important regulator of key membrane metabolisms in membrane biogenesis-demanding processes.

Received for publication, November 12, 2007 , and in revised form, September 2, 2008.

^* This work was supported in part by grants from the Aqencia Nacional de Promoción Cientifica y Tecnológíca Ministerío de Ciencia, Tecnología e Innovación Productiva de Argentina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), and Sectretaría de Ciencia y Tecnología-Universidad Nacional de Cordoba (to H. J. F. M., J. L. D., and B. L. C.), the J. S. McDonnell Foundation (to B. L. C.), and the Howard Hughes Medical Institute (to H. J. F. M.). 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 Both authors contributed equally to this work.

² Fellows of CONICET.

³ Career members of CONICET.

⁴ To whom correspondence should be addressed: Tel./Fax: 54-351-4334-074; E-mail: bcaputto{at}mail.fcq.unc.edu.ar.

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