Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1.
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 G(1) phase of the cell cycle. Ectopic expression studies using an inducible retroviral vector show that the G(1) 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 G(1) 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.
Kim
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HA
Departments of Microbiology, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Ratner
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N
Roberts
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TM
Stiles
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CD
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D025542:Neurofibromin 1; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection
D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D010982:Platelet-Derived Growth Factor; D019938:Cyclin D1; D005576:Colforsin; D000242:Cyclic AMP; D017479:Receptors, Platelet-Derived Growth Factor; D013752:Tetracycline