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The Journal of Neuroscience, February 15, 2001, 21(4):1110-1116

Schwann Cell Proliferative Responses to cAMP and Nf1 Are Mediated by Cyclin D1

Haesun A. Kim¹, Nancy Ratner³, Thomas M. Roberts², and Charles D. Stiles¹

Departments of ¹ Microbiology and Molecular Genetics and ² Pathology, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and ³ Department of Cell Biology, Neurobiology and Anatomy, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267

In most mammalian cells, the cAMP-dependent protein kinase A pathway promotes growth arrest and cell differentiation. However in Schwann cells, the reverse is true. Elevated levels of cAMP function as the cofactor to a broad range of mitogenic cues in culture and in animals. Previous studies have suggested that cAMP acts at an early point in the Schwann cell mitogenic response, perhaps by stimulating the expression of growth factor receptors. We show here that cAMP acts downstream rather than upstream of growth factor receptor expression. The essential function(s) of cAMP is exerted as Schwann cells progress through the G₁ phase of the cell cycle. Ectopic expression studies using an inducible retroviral vector show that the G₁ phase requirement for cAMP can be alleviated by a single protein, cyclin D1. We show, in addition, that at least one function of the Nf1 tumor suppressor is to antagonize the accumulation of cAMP and the expression of cyclin D1 in Schwann cells. Thus a G₁ phase-specific protein, cyclin D1, accounts for two salient features of Schwann cell growth control: the promitotic response to cAMP and the antimitotic response to the Nf1 tumor suppressor.

Key words: Schwann cell; platelet-derived growth factor; cAMP; cyclin D1; cell cycle; neurofibromatosis

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2141110-07$05.00/0

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